New piperazine compound and use thereof as a hcv polymerase inhibitor

ABSTRACT

The present invention relates to a compound represented by the following formula [I] 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof, or a solvate thereof and an anti-HCV agent and an HCV polymerase inhibitor containing this compound. The compound of the present invention shows an anti-HCV activity based on the HCV polymerase inhibitory activity, and useful as an agent for the prophylaxis or treatment of hepatitis C.

TECHNICAL FIELD

The present invention relates to a novel piperazine compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is useful as a therapeutic agent for hepatitis C. The present invention relates to an anti-HCV agent, which contains a piperazine compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is effective for the prophylaxis or treatment of hepatitis C and which shows anti-hepatitis C virus (HCV) activity, particularly anti-HCV activity based on an RNA-dependent RNA polymerase inhibitory activity.

BACKGROUND ART

In 1989, a main causative virus of non-A non-B posttransfusion hepatitis was found and named hepatitis C virus (HCV). Since then, several types of hepatitis viruses have been found besides type A, type B and type C, wherein hepatitis caused by HCV is called hepatitis C.

The patients infected with HCV are considered to involve several percent of the world population, and the infection with HCV characteristically becomes chronic.

HCV is an envelope RNA virus, wherein the genome is a single strand plus-strand RNA, and belongs to the genus Hepacivirus of Flavivirus. Of the same hepatitis viruses, for example, hepatitis B virus (HBV), which is a DNA virus, is eliminated by the immune system and the infection with this virus ends in an acute infection except for neonates and infants having yet immature immunological competence. In contrast, HCV somehow avoids the immune system of the host due to an unknown mechanism. Once infected with this virus, even an adult having a mature immune system frequently develops persistent infection.

When chronic hepatitis is associated with the persistent infection with HCV, it advances to cirrhosis or liver cancer in a high rate. Enucleation of tumor by operation does not help much, because the patient often develops recurrent liver cancer due to the sequela inflammation in non-cancerous parts. In addition, there is a report on the involvement of HCV infection in dermatosis such as chronic urticaria, lichen planus, cryoglobulinemic purpura and the like.

Thus, an effective therapeutic method of hepatitis C is desired. Apart from the symptomatic therapy to suppress inflammation with an anti-inflammatory agent, the development of a therapeutic agent that reduces HCV to a low level free from inflammation and that eradicates HCV has been strongly demanded.

At present, a treatment with interferon is the only effective method known for the eradication of HCV. However, interferon can eradicate the virus only in about one-third of the patient population. For the rest of the patients, it has no effect or provides only a temporary effect. In recent years, polyethylene glycolated interferon has been put to practical use, and enhanced effects and reduced side effects have been achieved. However, complete response rate still remains at a low level, and therefore, an anti-HCV drug to be used in the place of or concurrently with interferon is awaited in great expectation.

In recent years, Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) has become commercially available as a therapeutic agent for hepatitis C, which is to be used concurrently with interferon. It enhances the efficacy of interferon but only to a low efficacy rate, and a different novel therapeutic agent for hepatitis C is desired.

Also, an attempt has been made to potentiate the immunocompetence of the patient with an interferon agonist, an interleukin-12 agonist and the like, thereby to eradicate the virus, but an effective pharmaceutical agent has not been found yet.

In addition, the inhibition of HCV growth, wherein HCV-specific protein is targeted, has been drawing attention these days.

The gene of HCV encodes a protein such as serine protease, RNA helicase, RNA-dependent RNA polymerase and the like. These proteins function as a specific protein essential for the growth of HCV.

One of the specific proteins, RNA-dependent RNA polymerase (hereinafter to be also briefly referred to as an HCV polymerase), is an enzyme essential for the growth of the virus. The gene replication of HCV having a plus-strand RNA gene is considered to involve synthesis of a complementary minus-strand RNA by the use of the plus-strand RNA as a template and using the obtained minus-strand RNA as a template, amplifying the plus-strand RNA. The portion called NS5B of a protein precursor, that HCV codes for, has been found to show an RNA-dependent RNA polymerase activity, and is considered to play a central role in the HCV gene replication.

Therefore, an HCV polymerase inhibitor can be a target in the development of an anti-HCV drug, and the development thereof is eagerly awaited. However, an effective HCV polymerase inhibitor has not been developed yet, like in other attempts to develop an anti-HCV drug based on other action mechanisms. As the situation stands, no pharmaceutical agent can treat hepatitis C satisfactorily.

The following describes known compounds comparatively similar to the present invention.

WO2004/73599 (page 33, Table 1) discloses the following compound a and the like as anti-HCV agents (see patent document 1).

However, the compound of the present invention is not disclosed in the specification, and any description suggestive thereof is not found.

As references disclosing compounds other than for anti-HCV agents, which are comparatively similar to the compound of the present invention, the following can be mentioned.

WO2004/71390 (page 33, line 8) discloses the following compound b and the like as compounds usable for the treatment of dysmenorrhea and the like (see patent document 2).

WO2004/31182 (page 25, line 4) discloses the following compound c and the like as compounds usable for the treatment of infertility (see patent document 3).

WO2000/39119 (page 42, Example 28L) discloses the following compound d and the like as compounds usable for inhibiting abnormal growth of cells (see patent document 4).

U.S. Pat. No. 5,880,128 (columns 67-68, Example 24) discloses the following compound e and the like as compounds usable for inhibiting abnormal growth of cells (see patent document 5).

WO1999/37304 discloses the following compound f and the like as factor Xa inhibitors, and application to viral infections is exemplarily shown (see patent document 6).

WO2001/07436 discloses the following compound g and the like as factor Xa inhibitors, and application to viral infections is exemplarily shown (see patent document 7).

WO2005/86898 (page 95, Example 9) and US2005/234033 (page 37, Example 9) disclose the following compound h and the like as therapeutic agents for proliferative diseases (see patent document 8 and patent document 9).

WO2000/53596 (page 42, in Table 2) discloses the following compound i and the like as compounds having activity for the central nervous system and activity for inflammatory diseases and allergic diseases (see patent document 10).

WO1998/37079 (page 138, lines 19-20) discloses the following compound j and the like as therapeutic agents for the diseases caused by abnormal nitric oxide production, such as multiple sclerosis and the like (see patent document 11).

JP2001-294572 (page 297, Example 349) discloses the following compound k and the like as compounds having an antithrombotic effect (see patent document 12).

EP1104754 (Example A-33) and EP1031563 (Example 33) disclose the following compound l and the like as compounds having an antithrombotic effect (see patent document 3 and patent document 14).

As compounds other than for a pharmaceutical use, which are comparatively similar to the compound of the present invention, the following can be mentioned.

WO2001/54504 (FIG. 55) discloses the following compound m and the like as anthelmintics (see patent document 15).

Other document (Tetrahedron Letters, 39, 1295-98, 1998; page 1297, Table II) discloses the following compound n and the like, and its synthetic method is described (see non-patent document 1).

However, none of these references discloses the compound of the present invention, not to mention use of the compounds of these references as anti-HCV agents or description suggestive thereof.

-   [patent document 1] WO2004/73599 (page 33, Table 1) -   [patent document 2] WO2004/71390 (page 33, line 8) -   [patent document 3] WO2004/31182 (page 25, line 4) -   [patent document 4] WO2000/39119 (page 42, Example 28L) -   [patent document 5] U.S. Pat. No. 5,880,128 (columns 67-68, Example     24) -   [patent document 6] WO1999/37304 -   [patent document 7] WO2001/07436 -   [patent document 8] WO2005/86898 (page 95, Example 9) -   [patent document 9] US2005/234033 (page 37, Example 9) -   [patent document 10] WO2000/53596 (page 42, in Table 2) -   [patent document 11] WO1998/37079 (page 138, lines 19-20) -   [patent document 12] JP2001-294572 (page 297, Example 349) -   [patent document 13] EP1104754 (Example A-33) -   [patent document 14] EP1031563 (Example 33) -   [patent document 15] WO2001/54504 (FIG. 55) -   [non-patent document 1] Tetrahedron Letters, Vol. 39, pages 1295-98,     1998 (page 1297, Table II)

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Based on the findings from the preceding studies, it has been elucidated that a pharmaceutical agent having an anti-HCV activity is effective for the prophylaxis and treatment of hepatitis C, and particularly an anti-HCV agent having an inhibitory activity on RNA-dependent RNA polymerase of HCV can be a prophylactic and therapeutic agent effective against hepatitis C and a prophylactic and therapeutic agent for the disease caused by hepatitis C.

Accordingly, the present invention provides a pharmaceutical agent having an anti-HCV activity, particularly a pharmaceutical agent having an RNA-dependent RNA polymerase inhibitory activity.

Means for Solving the Problems

The present inventors have made an in-depth study of compounds having an anti-HCV activity, particularly RNA-dependent RNA polymerase inhibitory activity, and completed the present invention.

More particularly, the present invention provides the following.

[1] An anti-HCV agent comprising, as an active ingredient, a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring A is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and

R is

a hydrogen atom,

—COR¹, —COOR², —CONR³R⁴, —SO₂R⁵, —CO—COOR⁶, —CO—CH═CH—COOR¹¹,

—CO— (CH₂)_(a)—NH—R⁷, —CO— (CH₂)_(b)—NHCOR⁸, —CO—(CH₂)_(c)—NHCOOR⁹ (wherein R¹ to R⁹ and R¹¹ are the same or different and each is a hydrogen atom or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, and a, b and c are the same or different and each is an integer of 1 to 4),

—CO—CONH₂, —C(═NH)NH₂, —C(═S)NH₂,

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, or

wherein X is a bond, C₁₋₄ alkylene, —CO—(CH₂)_(p)—, —CONR¹⁰—(CH₂)_(q)—, —CO—(CH₂)_(r)—O—(CH₂)_(s)—, —CO—(CH₂)_(t)—NH—(CH₂)_(u)—, —CO—(CH₂)_(v)—CONH—(CH₂)_(w)—, or

—CO—NH—SO₂—,

ring C is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), R¹⁰ is a hydrogen atom, or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, p, q, r, s, u, v and w are the same or different and each is 0 or an integer of 1 to 4, and t is an integer of 1 to 4, group A: halogen atom, nitro group, cyano group,

—OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅

(wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, group B: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkoxy group, amino group, C₁₋₄ alkylamino group, di(C₁₋₄ alkyl)amino group, carboxyl group, C₁₋₄ alkoxy-carbonyl group, carbamoyl group, C₁₋₄ alkylamino-carbonyl group, di(C₁₋₄ alkyl)amino-carbonyl group, heterocyclyl-carbonyl group, and tri(C₁₋₄ alkyl)ammoniumyl group (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group C: halogen atom, cyano group, hydroxyl group, carboxyl group, C₁₋₄ alkyl group, halogeno C₁₋₄ alkyl group, hydroxy C₁₋₄ alkyl group, carboxy C₁₋₄ alkyl group, C₁₋₄ alkoxy C₁₋₄ alkyl group, C₁₋₄ alkoxy group, and carboxy C₁₋₄ alkoxy group. [2] The anti-HCV agent of [1], which comprises a compound represented by the following formula [I′] or a pharmaceutically acceptable salt thereof as an active ingredient:

wherein ring A′ is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A″, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A″ (wherein the heterocyclic group has, besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B′ is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A″, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A″ (wherein the heterocyclic group has, besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and

R′ is

a hydrogen atom,

—COR¹⁰¹, —COOR¹⁰², —CONR¹⁰³R¹⁰⁴, —SO₂R¹⁰⁵, —CO—COOR¹⁰⁶,

—CO—(CH₂)_(a)NH—R¹⁰⁷, —CO—(CH₂)_(b)—NHCOR¹⁰⁸, —CO—(CH₂)_(c)—NHCOOR¹⁰⁹ (wherein R¹⁰¹ to R¹⁰⁹ are the same or different and each is a hydrogen atom, or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B′, and a, b and c are the same or different and each is an integer of 1 to 4),

—CO—CONH₂, —C(═NH)NH₂, —C(═S)NH₂,

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B′, or

wherein X′ is a bond, alkylene, —CO—(CH₂)_(p)—, —CONR¹¹⁰—(CH₂)_(q)—, —CO—(CH₂)_(r)—O—(CH₂)_(s)—, —CO—(CH₂)_(t)—NH—(CH₂)_(u)—, or

—CO—NH—SO₂—,

ring C′ is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A″, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A″ (wherein the heterocyclic group has, besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), R¹¹⁰ is a hydrogen atom, or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B′, p, q, r, s and u are the same or different and each is 0 or an integer of 1 to 4, and t is an integer of 1 to 4, group A″: halogen atom, nitro group, cyano group,

—OR^(a101), —SR^(a102), —NR^(a103)R^(a104), —NHCOR^(a105), —COOR^(a106), —CONR^(a107)R^(a108), —SO₂NR^(a109)R^(a110), —COR^(a111), —SO₂R^(a112), —CONHSO₂R^(a113)

(wherein R^(a101) to R^(a113) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B′, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C′, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C′ (wherein the heterocyclic group has, besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C′), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B′, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C′, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C′ (wherein the heterocyclic group has, besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C′, group B′: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkoxy group, amino group, C₁₋₄ alkylamino group, di(C₁₋₄ alkyl)amino group, carboxyl group, C₁₋₄ alkoxy-carbonyl group, carbamoyl group, C₁₋₄ alkylamino-carbonyl group, di(C₁₋₄ alkylamino-carbonyl group, and heterocyclyl-carbonyl group (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group C′: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkyl group, halogeno C₁₋₄ alkyl group, and hydroxy C₁₋₄ alkyl group. [3] The anti-HCV agent of [1], wherein the ring A is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group A. [4] The anti-HCV agent of [1], wherein n is 1. [5] The anti-HCV agent of [1], wherein ring B is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group A. [6] The anti-HCV agent of [1], wherein R is

wherein each symbol is as defined in [1]. [7] The anti-HCV agent of [6], wherein X is a bond. [8] The anti-HCV agent of [6], wherein X is —CO—(CH₂)_(p)— wherein p is as defined in [1]. [9] The anti-HCV agent of [8], wherein p is 1. [10] The anti-HCV agent of [6], wherein X is —CONH—(CH₂)_(q)— wherein q is as defined in [1]. [11] The anti-HCV agent of [10], wherein q is 0. [12] The anti-HCV agent of [10], wherein q is 1. [13] The anti-HCV agent of [6], wherein ring C is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A. [14] An HCV polymerase inhibitor comprising a compound of any one of [1] to [13] or a pharmaceutically acceptable salt thereof as an active ingredient. [15] A compound represented by the following formula [I-A] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and group A is as defined in [1]), q1 is an integer of 1 to 4, and other symbols are as defined in [1]. [16] A compound represented by the following formula [I-B] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and group A is as defined in [1]), and other symbols are as defined in [1]. [17] A compound represented by the following formula [I-C] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and group A is as defined in [1]), and other symbols are as defined in [1]. [18.0] A compound represented by the following formula [I-D] or a pharmaceutically acceptable salt thereof:

wherein ring C2′ is a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A″′ (wherein the heterocyclic group has, besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and other symbols are as defined in [2]. group A″′: halogen atom, nitro group, cyano group,

—OR^(a101), —SR^(a102), —NR^(a103)R^(a104), —NHCOR^(a105), —COOR^(a106), —CONR^(a107)R^(a108), —SO₂NR^(a109)R^(a110), —COR^(a111), —SO₂R^(a112), —CONHSO₂R^(a113)

(wherein R^(a101) to R^(a113) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the above-mentioned group B′, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group C′, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the above-mentioned group C′ (wherein the heterocyclic group has, besides carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the above-mentioned group C′), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the above-mentioned group B′, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group C′, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the above-mentioned group C′. [18] A compound represented by the following formula [I-D1] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring B1 is a phenyl group optionally substituted by 1 to 5 substituents selected from group A (wherein group A is as defined in [1]), ring C2 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A′ (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and other symbols are as defined in [1], group A′: halogen atom, nitro group, cyano group,

—OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅

(wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C, and group B and group C are as defined in [1]. [19] The compound of any one of [15] to [18], wherein ring A is a phenyl group optionally substituted by 1 to 5 substituents selected from group A, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [20] The compound of any one of [15] to [18], wherein n is 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [21] The compound of any one of [15] to [17], wherein the ring B is a phenyl group optionally substituted by 1 to 5 substituents selected from group A, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [22] The compound of any one of [15] to [17], wherein the ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A, and the heterocyclic group is selected from the group consisting of piperidinyl group, morpholinyl group, pyrrolidinyl group, piperazinyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, oxadiazolyl group, pyridyl group and pyrimidinyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [23] The compound of [16], wherein the ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A, and the heterocyclic group is selected from the group consisting of thiazolyl group, isothiazolyl group, isoxazolyl group, thiadiazolyl group, oxadiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group and pyrimidinyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [24] The compound of [17], wherein the ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A, and the heterocyclic group is selected from the group consisting of piperidinyl group, morpholinyl group, pyrrolidinyl group, piperazinyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, isoxazolyl group, pyridyl group and pyrimidinyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [25] The compound of [18], wherein the ring C2 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A′, and the heterocyclic group is selected from the group consisting of imidazolinyl group, thiazolinyl group, oxazolinyl group, thienyl group, dioxopyrrolidinyl group, dioxopyrrolinyl group, oxopyrrolidinyl group, oxothiadiazolinyl group, tetrahydrobenzothiazolyl group, thiazolyl group, thiadiazolyl group, pyrazolyl group, imidazolyl group, triazolyl group, oxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group,

-   quinolyl group, -   [1,5]naphthyridinyl group, -   [1,6]naphthyridinyl group, -   oxopiperidinyl group, -   oxodihydropyridinyl group, -   [1,2,4]triazolo[1,5-a]pyrimidinyl group, -   benzimidazolyl group, -   imidazo[4,5-c]pyridinyl group, -   quinoxalinyl group, -   pyrido[2,3-b]pyrazinyl group, -   pyrido[3,4-b]pyrazinyl group, -   pteridinyl group, -   pyrazino[2,3-b]pyrazinyl group, -   imidazo[4,5-b]pyrazinyl group, -   2,2-dioxo-1,2,3,4-tetrahydropyrazino[2,3-c][1,2,6]thiadiazinyl     group, -   2-oxo-1,4-dihydropyrazino[2,3-d][1,3]oxazinyl group, -   2-oxo-2,3-dihydroimidazo[4,5-b]pyrazinyl group, -   [1,2,5]thiadiazolo[3,4-b]pyrazinyl group, -   benzothiazolyl group, -   4,5,6,7-tetrahydrobenzothiazolyl group, -   thiazolo[5,4-b]pyridinyl group, -   thiazolo[5,4-c]pyridinyl group, -   thiazolo[4,5-d]pyrimidinyl group, -   thiazolo[5,4-d]pyrimidinyl group, -   thiazolo[4,5-d]pyridazinyl group, -   thiazolo[4,5-b]pyrazinyl group, -   thiazolo[4,5-d][1,2,3]triazinyl group, -   5-oxo-4,5-dihydrothiazolo[5,4-b]pyridinyl group, -   pyrazolo[3,4-d]thiazolyl group, -   4,6-dioxo-5,6-dihydropyrrolo[3,4-d]thiazolyl group, -   4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl group, -   4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl group, -   4-oxo-4,5-dihydrothiazolo[5,4-c]pyridinyl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidinyl group, -   4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazinyl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazinyl group, -   4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazinyl group, -   4-oxo-3,4-dihydrothiazolo[4,5-d][1,2,3]triazinyl group, -   5-oxo-[1,3,4]thiadiazolo[3,2-a]pyrimidinyl group, -   7-oxo-[1,3,4]thiadiazolo[3,2-a]pyrimidinyl group, -   4-oxo-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazinyl group, -   [1,2,4]triazolo[3,4-b][1,3,4]thiadiazolyl group, and     indenothiazolyl group, or a pharmaceutically acceptable salt     thereof, or a solvate thereof.     [26] The compound of [25], wherein the ring C2 is a thiazol-2-yl     group optionally substituted by 1 to 5 substituents selected from     group A′, or a pharmaceutically acceptable salt thereof, or a     solvate thereof.     [27] The compound of [25], wherein the ring C2 is a heterocyclic     group optionally substituted by 1 to 5 substituents selected from     group A′, and the heterocyclic group is selected from the group     consisting of -   benzothiazol-2-yl group, -   4,5,6,7-tetrahydrobenzothiazol-2-yl group, -   thiazolo[5,4-b]pyridin-2-yl group, -   thiazolo[5,4-c]pyridin-2-yl group, -   thiazolo[4,5-d]pyrimidin-2-yl group, -   thiazolo[5,4-d]pyrimidin-2-yl group, -   thiazolo[4,5-d]pyridazin-2-yl group, -   thiazolo[4,5-b]pyrazin-2-yl group, -   thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl group, -   1H-pyrazolo[3,4-d]thiazol-5-yl group, -   4,6-dioxo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl group, -   4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[5,4-c]pyridin-2-yl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-oxo-3,4-dihydrothiazolo[4,5-d][1,2,3]triazin-6-yl group, -   5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl group, -   [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl group, and     indenothiazolyl group, or a pharmaceutically acceptable salt     thereof, or a solvate thereof.     [28] The compound of [25], wherein the ring C2 is a pyrazin-2-yl     group optionally substituted by 1 to 5 substituents selected from     group A′, or a pharmaceutically acceptable salt thereof, or a     solvate thereof.     [29] The compound of [25], wherein the ring C2 is a heterocyclic     group optionally substituted by 1 to 5 substituents selected from     group A′, and the heterocyclic group is selected from the group     consisting of -   quinoxalin-2-yl group, -   pyrido[2,3-b]pyrazin-2-yl group, -   pyrido[2,3-b]pyrazin-3-yl group, -   pyrido[3,4-b]pyrazin-2-yl group, -   pteridin-6-yl group, -   pteridin-7-yl group, -   pyrazino[2,3-b]pyrazin-2-yl group, -   1H-imidazo[4,5-b]pyrazin-5-yl group, -   2,2-dioxo-1,2,3,4-tetrahydropyrazino[2,3-c][1,2,6]thiadiazin-7-yl     group, -   2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl group, -   2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl group, and -   [1,2,5]thiadiazolo[3,4-b]pyrazinyl group, or a pharmaceutically     acceptable salt thereof, or a solvate thereof.     [30] The compound of [16], which is selected from the group     consisting of -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide (Example 3), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyridin-3-ylamide (Example 211), -   (R)-4-(4-propyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid     3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide (Example 295), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyrimidin-4-ylamide (Example     300), -   4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic     acid tert-butyl ester (Example 301), -   4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic     acid hydrochloride (Example 314), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide (Example 318), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-[1,3,4]thiadiazol-2-ylamide     (Example 332), -   5-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-[1,3,4]oxadiazole-2-carboxylic     acid ethyl ester (Example 334), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide (Example 347), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-[1,3,4]oxadiazol-2-ylamide     (Example 348), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-propyl-benzylamide) 1-pyridin-4-ylamide (Example 436), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-propyl-benzylamide) 1-[1,3,4]thiadiazol-2-ylamide (Example     437), -   (2-{[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-thiazol-4-yl)-acetic     acid ethyl ester (Example 470), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid     1-{[4-(2-morpholin-4-yl-2-oxo-ethyl)-thiazol-2-yl]-amide}3-(4-propyl-benzylamide)     (Example 475), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid     1-{[4-(2-hydroxy-ethyl)-thiazol-2-yl]-amide}3-(4-propyl-benzylamide)     (Example 476), -   5-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-[1,3,4]thiadiazole-2-carboxylic     acid ethyl ester (Example 477), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(5-hydroxymethyl-[1,3,4]thiadiazol-2-yl)-amide] (Example 482), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(5-acetyl-[1,3,4]thiadiazol-2-yl)-amide]     3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 483), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[5-(1-hydroxy-1-methyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide}     (Example 484), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(5-methyl-[1,3,4]thiadiazol-2-yl)-amide] (Example 488), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amide] (Example 489), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-methoxy-pyridin-4-yl)-amide] (Example 490), -   4-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic     acid tert-butyl ester (Example 491), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}     (Example 495), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[5-(4-hydroxy-piperidine-1-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}     (Example 496), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[5-(morpholine-4-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}     (Example 497), -   4-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic     acid (Example 502), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-carbamoyl-pyridin-4-yl)-amide]     3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 503), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-dimethylcarbamoyl-pyridin-4-yl)-amide] (Example 504), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-hydroxymethyl-pyridin-4-yl)-amide] (Example 511), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-cyclopropylcarbamoyl-pyridin-4-yl)-amide]     3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 512), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[2-(morpholine-4-carbonyl)-pyridin-4-yl]-amide} (Example 513), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[2-(pyrrolidine-1-carbonyl)-pyridin-4-yl]-amide} (Example 514), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-chloro-pyridin-4-yl)-amide]     3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 517), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-4-ylamide     (Example 525), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(5-methyl-isoxazol-3-yl)-amide] (Example 526), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(3-methyl-[1,2,4]thiadiazol-5-yl)-amide] (Example 527), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(3-methyl-isoxazol-5-yl)-amide] (Example 528), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[1,2,4]triazol-4-ylamide (Example 539), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(5-methyl-[1,3,4]thiadiazol-2-yl)-amide]     3-(4-pentafluoroethyl-benzylamide) (Example 552), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(3-methyl-isothiazol-5-yl)-amide] (Example 553), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-2-ylamide     (Example 554), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-trifluoromethyl-pyridin-4-yl)-amide] (Example 555), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(1H-[1,2,4]triazol-3-yl)-amide] (Example 565), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2H-tetrazol-5-yl)-amide] (Example 566), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-methyl-thiazol-4-yl)-amide] (Example 567), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(1-methyl-1H-pyrazol-3-yl)-amide] (Example 569), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-5-ylamide     (Example 607), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-amide} (Example 612),     and -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(5-bromo-[1,3,4]thiadiazol-2-yl)-amide]     3-(4-trifluoromethoxy-benzylamide) (Example 936),     or a pharmaceutically acceptable salt thereof, or a solvate thereof.     [31] The compound of [17], which is selected from the group     consisting of -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 2), -   1-(4-iodo-benzenesulfonyl)-4-(2-piperidin-1-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 102), -   1-(4-iodo-benzenesulfonyl)-4-(2-morpholin-4-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 104), -   1-(4-iodo-benzenesulfonyl)-4-(2-pyridin-2-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 153), -   1-(4-iodo-benzenesulfonyl)-4-(2-pyridin-3-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 154), -   (R)-1-(4-iodo-benzenesulfonyl)-4-(2-piperidin-1-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 158), -   (R)-1-(4-iodo-benzenesulfonyl)-4-(2-pyrrolidin-1-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 159), -   (R)-1-(4-iodo-benzenesulfonyl)-4-(2-morpholin-4-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 160), -   (R)-4-(2-pyridin-3-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 175), -   (R)-4-(2-morpholin-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 180), -   (R)-4-(2-1H-imidazol-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 195), -   (R)-4-(2-imidazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 219), -   (R)-4-(2-[1,2,3]triazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 220), -   (R)-4-(2-pyrazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 228), -   (R)-4-(2-[1,2,4]triazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 229), -   (R)-4-(2-[1,2,4]triazol-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 230), -   (R)-4-(2-[1,2,3]triazol-2-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 242), -   (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 257), -   (R)-4-(2-1H-tetrazol-5-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 261), -   (R)-4-(2-tetrazol-2-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 278), -   (2-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic     acid ethyl ester (Example 309), -   (2-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic     acid (Example 310), -   (1-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-tetrazol-5-yl)-acetic     acid ethyl ester (Example 311), -   (1-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-tetrazol-5-yl)-acetic     acid (Example 312), -   1-(4-iodo-benzenesulfonyl)-4-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 346), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 409), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 410), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 411), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 412), -   (2-{2-oxo-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-2H-tetrazol-5-yl)-acetic     acid ethyl ester (Example 455), -   (R)-4-[2-(5-methyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 456), -   (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 457), -   (R)-4-(2-tetrazol-2-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 460), -   (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 461), -   (R)-4-(2-imidazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 462), -   (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 464), -   (2-{2-oxo-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-2H-tetrazol-5-yl)-acetic     acid (Example 465), -   (2-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic     acid ethyl ester (Example 466), -   (R)-4-[2-(5-methyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 467), -   (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 468), -   (R)-4-[2-(5-phenyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 479), -   (R)-4-[2-(3-methyl-isoxazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 480), -   (R)-4-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 498), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 500), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 508), -   (R)-4-[2-(2-methyl-2H-tetrazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid -   4-(1,1-difluoro-propyl)-benzylamide (Example 518), -   (R)-4-[2-(1-methyl-1H-tetrazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 519), -   (5-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-tetrazol-2-yl)-acetic     acid ethyl ester (Example 532), -   (5-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-tetrazol-1-yl)-acetic     acid ethyl ester (Example 533), -   (R)-4-[2-(5-isopropyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 541), -   (R)-4-[2-(5-isopropyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 542), -   (R)-4-{2-[5-(2-morpholin-4-yl-2-oxo-ethyl)-tetrazol-2-yl]-acetyl}-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 543), -   (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-pentafluoroethyl-benzylamide (Example 551), -   (R)-4-(2-pyrimidin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 590), -   (R)-4-[2-(5-amino-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 1096), and -   (R)-4-[2-(5-amino-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 1097),     or a pharmaceutically acceptable salt thereof, or a solvate thereof.     [32] The compound of [18], which is selected from the group     consisting of -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid tert-butyl ester (Example 5), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 6), -   (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 7), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 8), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 9), -   2-[(R)-3-[(6-isopropyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 13), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(2-fluoro-4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 14), -   4-(4,5-dihydro-1H-imidazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 103), -   4-(4,5-dihydro-thiazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 112), -   1-(4-isopropyl-benzenesulfonyl)-4-(4-methyl-thiazol-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 115), -   4-(4,5-dihydro-oxazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 133), -   4-benzothiazol-2-yl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 134), -   1-(4-isopropyl-benzenesulfonyl)-4-(4-phenyl-thiazol-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 135), -   (R)-4-(2,5-dioxo-pyrrolidin-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 147), -   (R)-4-(2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 148), -   4-(8H-indeno[1,2-d]thiazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 155), -   1-(4-isopropyl-benzenesulfonyl)-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 156), -   2-[4-(4-isopropyl-benzenesulfonyl)-3-(4-trifluoromethyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid ethyl ester (Example 170), -   2-[4-(4-isopropyl-benzenesulfonyl)-3-(4-trifluoromethyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 171), -   (R)-4-(4,5-dihydro-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 179), -   (R)-4-(4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 184), -   (R)-4-benzothiazol-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 191), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 244), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid methyl ester (Example 254), -   {2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-acetic     acid methyl ester (Example 255), -   {2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-acetic     acid (Example 259), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid ethyl ester (Example 296), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid methyl ester (Example 297), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 298), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 299), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid methyl ester (Example 302), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid methyl ester (Example 303), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 315), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid tert-butyl ester (Example 319), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid tert-butyl ester (Example 320), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 322), -   4-hydroxy-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic     acid ethyl ester (Example 325), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid tert-butyl ester (Example 326), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid trifluoroacetate (Example 327), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 328), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 329), -   2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid tert-butyl ester (Example 330), -   2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 331), -   (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-propyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 333), -   2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 335), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic     acid benzyl ester (Example 336), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic     acid methyl ester (Example 337), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic     acid (Example 338), -   4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 339), -   (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 340), -   4-methyl-2-[(R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 341), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic     acid (Example 342), -   2-[(R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 343), -   2-[(R)-4-(4-isopropyl-benzenesulfonyl)-3-(4-isopropyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 344), -   (R)-4-(2-oxo-pyrrolidin-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 345), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-isonicotinic     acid trifluoroacetate (Example 349), -   (R)-4-(1-methyl-1H-imidazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 352), -   (R)-4-(1H-imidazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 353), -   (R)-4-(4-methyl-5-methylcarbamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 354), -   (R)-4-(5-dimethylcarbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 355), -   2-[(R)-3-(4-cyclopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 356), -   4-hydroxy-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic     acid (Example 357), -   ({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-acetic     acid tert-butyl ester (Example 358), -   3-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic     acid tert-butyl ester (Example 359), -   ({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-acetic     acid (Example 360), -   3-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic     acid (Example 361), -   (R)-4-(5-nitro-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 362), -   4-ethyl-2-[(R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 363), -   2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 364), -   4-methyl-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 365), -   2-[(R)-3-(4-ethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 366), -   2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 367), -   (R)-4-(5-amino-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 368), -   (R)-2-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic     acid (Example 369), -   (S)-2-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic     acid (Example 370), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-oxazole-5-carboxylic     acid trifluoroacetate (Example 371), -   (R)-4-(5-bromo-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 372), -   (R)-4-(2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 373), -   (R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 374), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid (Example 376), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic     acid 5′-amide 3-(4-isopropyl-benzylamide) (Example 377), -   4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 378), -   2-[(R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid hydrochloride (Example 379), -   3-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-propionic     acid (Example 382), -   2-[(R)-3-(4-cyclopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 383), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 385), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 386), -   2-[(R)-3-[(6-dimethylamino-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 387), -   4-methyl-2-[(R)-3-[(6-propyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 388), -   2-[(R)-3-[(6-azetidin-1-yl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 389), -   4-methyl-2-[(R)-3-[(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 390), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methoxymethyl-thiazole-5-carboxylic     acid (Example 394), -   2-[(R)-3-(4-azetidin-1-yl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 398), -   (R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 399), -   2-[(R)-3-benzylcarbamoyl-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 401), -   (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 406), -   (R)-3-[(6-dimethylamino-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 407), -   (R)-3-[(6-isopropyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 408), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 414), -   (R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 415), -   4-methyl-2-[(R)-3-(4-pyrrolidin-1-yl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 416), -   6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid (Example 417), -   4-methyl-2-[(R)-3-phenethylcarbamoyl-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 418), -   (R)-6′-amino-3′-chloro-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 420), -   (R)-6′-bromo-3′-chloro-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 421), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-3′,6′-dimethyl-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 422), -   (R)-6′-amino-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 423), -   2-[(R)-3-[4-(ethyl-methyl-amino)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 424), -   2-[(R)-3-(4-diethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 425), -   5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2H-pyrazole-3-carboxylic     acid (Example 426), -   4-chloro-5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2H-pyrazole-3-carboxylic     acid (Example 427), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-3′-methyl-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 431), -   (R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 432), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-5-methyl-thiazole-4-carboxylic     acid (Example 434), -   5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-1-methyl-1H-pyrazole-3-carboxylic     acid (Example 439), -   (R)-4-(4-propyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 440), -   (R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 441), -   2-[(R)-3-(4-ethoxy-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 442), -   (R)-6′-amino-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 443), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-trifluoromethyl-thiazole-5-carboxylic     acid ethyl ester (Example 444), -   5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-methyl-2H-pyrazole-3-carboxylic     acid (Example 445), -   (R)-4-(5-methanesulfonylaminocarbonyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 446), -   (R)-4-(5-methanesulfonylaminocarbonyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 447), -   2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 448), -   (R)-6′-methyl-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 449), -   2-[(R)-3-(4-methoxymethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 451), -   (R)-4-(5-hydroxymethyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 452), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-trifluoromethyl-thiazole-5-carboxylic     acid (Example 453), -   (R)-4-(6-hydroxy-5-methyl-pyridazin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 454), -   (R)-4-(5-amino-pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 458), -   (R)-5′-amino-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-isopropyl-benzylamide (Example 471), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 472), -   (R)-3-(4-methoxymethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 473), -   (R)-3-(2-chloro-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 474), -   (R)-4-(4-ethyl-benzenesulfonyl)-5′-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 478), -   (R)-3-(2-chloro-4-propyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 485), -   4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid methyl ester (Example 486), -   4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid (Example 487), -   {4-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrazol-1-yl}-acetic     acid (Example 493), -   4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid amide (Example 494), -   4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(3-propyl-4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 499), -   (R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 501), -   (R)-4-(5-dimethylaminomethyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 505), -   (R)-4-(4-methyl-5-methylaminomethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 506), -   (R)-6′-amino-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 507), -   2-[(R)-4-(3-fluoro-4-trifluoromethoxy-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 509), -   (R)-4-(4-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 510), -   (R)-6′-acetylamino-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 515), -   (R)-4-(5-oxo-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 516), -   (R)-4-(5-methyl-1H-pyrazol-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 523), -   (R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 524) -   (R)-5′-amino-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 530), -   (R)-4-(4-methyl-5-pyrrolidin-1-ylmethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 531), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic     acid benzyl ester (Example 534), -   5-hydroxymethyl-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 535), -   5-methoxymethyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 536), -   5-hydroxymethyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 537), -   (R)-5′-dimethylaminomethyl-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 538), -   (R)-5′-methanesulfonylamino-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 544), -   (R)-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 545), -   (R)-4-(6-hydroxy-pyridazin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 546), -   6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid amide (Example 547), -   (R)-4-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 548), -   (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 549), -   (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 556), -   (R)-4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 557), -   (R)-5′-pyrrolidin-1-ylmethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 558), -   (R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 559), -   (R)-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 560), -   (R)-4-(5-benzyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 561), -   (R)-4-(4,5-bis-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 562), -   (R)-4-(3-methyl-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 563), -   (R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 564), -   (R)-4-(5-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 570), -   (R)-4-(6-chloro-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 571), -   (R)-4-pyrimidin-4-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 572), -   (R)-4-(4,6-dioxo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 573), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 574), -   (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 575), -   (R)-4-(3-methyl-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 576), -   (R)-4-(5-cyano-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 577), -   (R)-4-(4-oxo-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 578), -   (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 579), -   (R)-4-pyrimidin-4-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 580), -   (R)-4-(2-hydroxy-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 581), -   4-amino-2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid ethyl ester (Example 582), -   (R)-4-(2-amino-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 584), -   (R)-4-(4-amino-pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 585), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic     acid 5′-amide 3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 586), -   2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic     acid tert-butyl ester (Example 587), -   (R)-4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 588), -   (R)-4-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 589), -   (R)-5′-cyano-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 591), -   (R)-5′-morpholin-4-ylmethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 593), -   (R)-5′-(4-methyl-piperazin-1-ylmethyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 594), -   (R)-5′-dimethylaminomethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 595), -   (R)-4-(3-acetylamino-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 596), -   (R)-4-(4-oxo-4,5-dihydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 597), -   (R)-4-(5-methanesulfonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 600), -   2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic     acid ethylamide (Example 601), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 602), -   2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-hydroxymethyl-thiazole-5-carboxylic     acid (Example 603), -   (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 604), -   (R)-4-(6-amino-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 605), -   (R)-4-(3-methoxy-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 606), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 615), -   (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 616), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 617), -   (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 618), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(ethyl-methyl-amino)-benzylamide (Example 619), -   5-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridine-2-carboxylic     acid (Example 620), -   (R)-4-(3-methoxy-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 625), -   (R)-4-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 626), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 627), -   (R)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 628), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-chloro-benzylamide (Example 629), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (6-dimethylamino-pyridin-3-ylmethyl)-amide (Example 630), -   5-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridine-2-carboxylic     acid (Example 631), -   (R)-4-quinoxalin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 632), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 633), -   (R)-6′-amino-5′-aminomethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 638), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (benzoxazol-2-ylmethyl)-amide (Example 639), -   (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 640), -   (R)-4-(6-hydroxy-[1,2,5]thiadiazolo[3,4-b]pyrazin-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 647), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 648), -   (R)-4-(2,2-dioxo-1,2,3,4-tetrahydro-2λ⁶-pyrazino[2,3-c][1,2,6]thiadiazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 650), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-ethoxy-benzylamide (Example 651), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-thiophen-2-yl-benzylamide (Example 652), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-bromo-benzylamide (Example 653), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 656) -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxymethyl-benzylamide (Example 657), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxy-benzylamide (Example 658), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid ([2,2′]bithiophenyl-5-ylmethyl)-amide (Example 659), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 660), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methylsulfanyl-benzylamide (Example 661), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (1-propyl-1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide (Example     662), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (biphenyl-4-ylmethyl)-amide (Example 663), -   (R)-4-(4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 664), -   (R)-4-(1H-imidazo[4,5-b]pyrazin-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 676), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-oxo-1-propyl-1,2-dihydro-pyridin-4-ylmethyl)-amide (Example     680), -   (R)-1-(4-bromo-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 683), -   (R)-4-(6-bromo-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 684), -   (R)-4-(7-bromo-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 685), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 686), -   (R)-4-(4-bromo-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 687), -   (R)-4-(6-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 688), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 689), -   (R)-4-pyrazino[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 690), -   (R)-4-[1,2,5]thiadiazolo[3,4-b]pyrazin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 691), -   (R)-4-(2-methyl-pteridin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 692), -   2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic     acid ethyl ester (Example 693), -   (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 694), -   (R)-1-(4-tert-butyl-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 695), -   (R)-1-(biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 696), -   (R)-1-(4-chloro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 697), -   (R)-1-(4-nitro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 698), -   (R)-4-(4-tert-butyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 700), -   (R)-4-(biphenyl-4-sulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 701), -   (R)-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 704), -   (R)-4-pteridin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 707), -   (R)-1-(4-iodo-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 708), -   (R)-4-pteridin-7-yl-1-(4-thiophen-2-yl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 709), -   3-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic     acid ethyl ester (Example 710), -   3-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic     acid (Example 711), -   2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic     acid (Example 712), -   (R)-1-(4-chloro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 713), -   (R)-1-(4-tert-butyl-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 714), -   (R)-4-thiazolo[5,4-c]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 715), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (6-propyl-pyridin-3-ylmethyl)-amide (Example 720), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-methyl-pyrazin-2-ylmethyl)-amide (Example 721), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-amino-4-propyl-benzylamide (Example 722), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-hydroxy-4-propyl-benzylamide (Example 723), -   (R)-1-(2′-hydroxy-biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 724), -   (R)-1-(3′-hydroxy-biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 725), -   (R)-1-(4-nitro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 726), -   (R)-1-(biphenyl-4-sulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 727), -   5-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiophene-2-carboxylic     acid tert-butyl ester (Example 728), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide (Example 730), -   (4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-2-yloxy)-acetic     acid (Example 731), -   (4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-3-yloxy)-acetic     acid (Example 732), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 735), -   (R)-1-(4-dimethylamino-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 736), -   (R)-4-thiazolo[5,4-b]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 739), -   (R)-4-[1,6]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 740), -   (R)-4-(5-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 741), -   (R)-4-(8-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 742), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-pyrrolidin-1-yl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 743), -   trans-[4-(4-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-phenyl)-cyclohexyl]-acetic     acid (Example 744), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 745), -   (R)-1-(4-morpholin-4-yl-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 746), -   (R)-1-(4-methoxy-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 747), -   (R)-4-pyrido[2,3-b]pyrazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 748), -   (R)-4-pyrazino[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 749), -   (R)-4-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 750), -   (R)-1-[4-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 751), -   (R)-1-(4-chloro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 752), -   4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-3-carboxylic     acid (Example 753), -   (R)-1-(4-nitro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 754), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-pyrrolidin-1-yl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 755), -   (R)-4-(3H-imidazo[4,5-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 756), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 757), -   (R)-4-(1H-benzimidazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 758), -   (R)-1-[4-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 759), -   (R)-4-pyrido[2,3-b]pyrazin-3-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 760), -   (R)-4-pyrido[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 761), -   (R)-4-pyrido[2,3-b]pyrazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 762), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(2,2,2-trifluoro-ethoxy)-benzylamide (Example 763), -   (methyl-{4-[(R)-4-pyrido[3,4-b]pyrazin-2-yl-2-(4-trifluoromethoxy-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenyl}-amino)-acetic     acid ethyl ester (Example 764), -   (methyl-{4-[(R)-4-pyrido[3,4-b]pyrazin-2-yl-2-(4-trifluoromethoxy-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenyl}-amino)-acetic     acid (Example 765), -   (R)-4-(5-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 766), -   (R)-4-(2-methyl-pteridin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 767), -   (R)-4-thiazolo[5,4-c]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 768), -   (R)-4-pyrido[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 769), -   (R)-4-pyrido[2,3-b]pyrazin-3-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 770), -   (R)-4-[1,6]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 771), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethylsulfanyl-benzylamide (Example 772), -   4-{5-[(R)-2-(4-propyl-benzylcarbamoyl)-4-pteridin-7-yl-piperazine-1-sulfonyl]-2-trifluoromethoxy-phenyl}-butyric     acid (Example 773), -   6-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-nicotinic     acid (Example 774), -   (R)-4-thiazolo[5,4-b]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 776), -   (R)-1-(4-iodo-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 777), -   (R)-1-(3′-hydroxy-biphenyl-4-sulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 778), -   {4′-[(R)-2-(4-propyl-benzylcarbamoyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-1-sulfonyl]-biphenyl-3-yloxy}-acetic     acid (Example 779), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 780), -   3-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 781), -   (R)-4-quinoxalin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 782), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 784), -   (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 785), -   (R)-4-(4-ethyl-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 786), -   (R)-4-(4-pyrrolidin-1-yl-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 788), -   (R)-1-(4-nitro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 790), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 791), -   (R)-4-[1,5]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 793), -   (R)-4-thiazolo[4,5-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 794), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamide (Example     795), -   (R)-4-(4-ethyl-benzenesulfonyl)-5′-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 796), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 2,4,6-trichloro-benzylamide (Example 797), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(2-trifluoromethyl-pteridin-7-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 798), -   (R)-4-(8-bromo-pyrido[3,4-b]pyrazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 799), -   (R)-4-(5,7-dichloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 800), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 801), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 802), -   (R)-4-(4,7-dioxo-4,5,6,7-tetrahydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 803), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (adamantan-1-ylmethyl)-amide (Example 804), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 805), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 806), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid amide (Example 807), -   3-{2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazin-8-yl}-propionic     acid (Example 808), -   (R)-6′-methyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 809), -   (R)-4-[8-(2-carbamoyl-ethyl)-pyrido[3,4-b]pyrazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 810), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (3-phenyl-propyl)-amide (Example 811), -   (R)-1-(4-ethyl-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 812), -   (R)-4-(8-bromo-pyrido[3,4-b]pyrazin-2-yl)-1-(4-ethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 813), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 814), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 815), -   3-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 816), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 817), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-benzothiazole-4-carboxylic     acid (Example 818), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 819), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 820), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 821), -   2-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid (Example 822), -   5-fluoro-2-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid (Example 823), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 824), -   (R)-1-(4-nitro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 825), -   3-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-propionic     acid (Example 826), -   (R)-4-(4-methyl-5-sulfamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 827), -   (R)-4-(4-methyl-5-methylsulfamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 828), -   (R)-4-(5-dimethylsulfamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 829), -   (R)-4-(5-acetylsulfamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 832), -   (R)-1-(4-nitro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 835), -   2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 836), -   (R)-4-(4-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 839), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-dimethyl-propyl)-benzylamide (Example 840), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-butyl-benzylamide (Example 841), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 842), -   2-[(R)-4-(4-nitro-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 843), -   2-[(R)-4-(4-tert-butyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 844), -   2-[(R)-4-(4-chloro-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 845), -   {4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-oxo-acetic     acid ethyl ester (Example 846), -   4-chloro-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 847), -   {4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-oxo-acetic     acid (Example 848), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-phenyl-cyclopropylmethyl)-amide (Example 849), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(2-methoxy-1,1-dimethyl-ethyl)-benzylamide (Example 851), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic     acid 5′-ethylamide 3-(4-trifluoromethoxy-benzylamide) (Example 852), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic     acid 5′-tert-butylamide 3-(4-trifluoromethoxy-benzylamide) (Example     853), -   2-[(R)-3-[4-(1,1-dimethyl-propyl)-benzylcarbamoyl]-4-(4-ethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 854), -   2-[(R)-3-(4-butyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 855), -   hydroxy-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-acetic     acid ethyl ester (Example 856), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-propyl-thiophen-2-ylmethyl)-amide (Example 857), -   (R)-4-(4-methyl-5-methylaminooxalyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 859), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid ethyl ester (Example 862), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid (Example 863), -   (R)-1-(4-fluoro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 864), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid methylamide (Example 865), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid dimethylamide (Example 866), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (1-phenyl-azetidin-3-ylmethyl)-amide (Example 867), -   4-chloro-2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 868), -   (R)-4-(7-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 869), -   (R)-4-(4-hydroxymethyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 870), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid isopropylamide (Example 871), -   (R)-4-(8-cyano-pyrido[3,4-b]pyrazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 872), -   (R)-1-(4-chloro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 873), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid (Example 874), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid methylamide (Example 875), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid amide (Example 876), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 877), -   (R)-4-(5-hydroxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 878), -   (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 879), -   7-chloro-2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid ethyl ester (Example 880), -   (R)-1-(4-bromo-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 881), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1-methoxymethyl-cyclopropyl)-benzylamide (Example 882), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(ethyl-methyl-amino)-benzylamide (Example 883), -   (R)-1-(4-methoxy-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 884), -   (R)-4-thiazolo[5,4-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 885), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 886), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 887), -   (R)-4-(5,7-dihydroxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 888), -   4-chloro-2-[(R)-3-[4-(1,1-dimethyl-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 890), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid ethyl ester (Example 891), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid (Example 892), -   (R)-4-(4-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 893), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 894), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 895), -   (R)-4-(7-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 896), -   (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 897), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1,2,2-tetrafluoro-ethoxy)-benzylamide (Example 898), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (3-phenyl-cyclobutylmethyl)-amide (Example 899), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 900), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (naphthalen-2-ylmethyl)-amide (Example 901), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 902), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 903), -   (R)-4-(6-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 904), -   (R)-4-(5-methoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 905), -   (R)-4-(7-chloro-4-methyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 906), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 907), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 908), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (4-methyl-2-propyl-thiazol-5-ylmethyl)-amide (Example 909), -   (R)-4-(5-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 910), -   (R)-4-(5-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 911), -   (R)-4-(5-bromo-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 912), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 913), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 914), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid amide (Example 915), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid methylamide (Example 916), -   (R)-4-(4-methyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 917), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 918), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 919), -   (R)-4-(7-methyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 920), -   (R)-4-(5-methyl-thiazolo[5,4-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 921), -   (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 922), -   (R)-4-(6-oxo-piperidin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 923), -   (R)-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide hydrochloride (Example 924), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 925), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 926), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 927), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 928), -   (R)-4-(5-methoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 929), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid dimethylamide (Example 930), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 931), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 932), -   (R)-4-(3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 933), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 934), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 935), -   (R)-4-(4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 937), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(difluoro-methoxy-methyl)-benzylamide (Example 938), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxymethyl-benzylamide (Example 939), -   (R)-4-(4-hydroxymethyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 940), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 941), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 942), -   (R)-4-(5-amino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 943), -   (R)-4-(7-methoxy-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 944), -   (R)-4-(5-dimethylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 945), -   (R)-4-[5-(2-hydroxy-ethylamino)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 946), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylic     acid methyl ester (Example 948), -   (R)-4-(5-ethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 949), -   (R)-4-(5-ethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 950), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(3-trifluoromethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 951), -   (R)-4-(5-methylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 952), -   (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 953), -   (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 954), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 955), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 956), -   (R)-4-(5-methyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 957), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(ethyl-methyl-amino)-benzylamide (Example 958), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 959), -   (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 960), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 961), -   (R)-4-(7-amino-5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 962), -   (R)-4-(5-chloro-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 963), -   (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 964), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxy-benzylamide (Example 965), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-fluoromethoxy-benzylamide (Example 966), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-fluoromethoxy-benzylamide (Example 967), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 968), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 969), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 970), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 971), -   (R)-4-(5-fluoro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 972), -   (R)-4-(5-isopropylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 973), -   (R)-4-(5-bromo-7-diethylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 974), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 975), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 976), -   (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 977), -   (R)-4-(5-acetyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 978), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid amide (Example 979), -   (R)-4-(1,3-dimethyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 980), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 981), -   (R)-4-(7-amino-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 982), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 983), -   (R)-4-(5-isopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 984), -   (R)-4-(4-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 985), -   (R)-4-(3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 986), -   (R)-4-thiazolo[4,5-d][1,2,3]triazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 987), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (indolizin-2-ylmethyl)-amide (Example 989), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylic     acid methylamide (Example 990), -   (R)-4-(5-isopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 991), -   (R)-4-(5-cyclopropylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 992), -   (R)-4-(5-chloro-2-diethylamino-thiazolo[4,5-d]pyrimidin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 993), -   (R)-4-[5-(3-hydroxy-3-methyl-but-1-ynyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 994), -   (R)-4-(5-ethynyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 995), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-pentafluorosulfanyl-benzylamide (Example 996), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 997), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 998), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 999), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1000), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1001), -   (R)-4-[4-(2-hydroxy-ethylamino)-thiazolo[4,5-d][1,2,3]triazin-6-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1002), -   (R)-4-(7-oxo-5-trifluoromethyl-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1003), -   (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1004), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1005), -   (R)-4-thiazolo[4,5-d][1,2,3]triazin-6-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1006), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid ethyl ester (Example 1007), -   (R)-4-(5-hydroxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1008), -   (R)-4-(4-methoxy-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1009), -   (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1010), -   (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1011), -   (R)-4-(5-cyclopropylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1012), -   2-[(R)-3-(4-trifluoromethoxy-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid amide (Example 1013), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1014), -   (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1015), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1016), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1017), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1018), -   (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1019), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1020), -   (R)-4-(7-amino-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1021), -   (R)-4-(7-methoxy-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1022), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1023), -   (R)-4-(5-tert-butyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1024), -   (R)-4-(5-tert-butyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1025), -   (R)-4-(6-chloro-5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1026), -   (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1027), -   (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1028), -   5-methyl-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-7-carboxylic     acid amide (Example 1029), -   (R)-4-(5-methyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-1-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1030), -   (R)-4-(4-oxo-3-trifluoromethyl-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1031), -   (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1032), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid (Example 1033), -   (R)-4-(4-amino-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1034), -   (R)-4-(4-methoxy-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1035), -   (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1036), -   (R)-4-(5-ethyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1037), -   (R)-4-(5-oxo-7-trifluoromethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1038), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1039), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 1040), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid dimethylamide (Example 1041), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 1042), -   (R)-4-(5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1043), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 1044), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 1045), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid methylamide (Example 1046), -   (R)-4-[5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1047), -   (R)-4-(5-acetyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1048), -   (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1049), -   (R)-4-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1050), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1051), -   (R)-4-(5-hydroxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1052), -   (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1053), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid methoxy-methyl-amide (Example 1054), -   (R)-4-(7-amino-5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1055), -   (R)-4-(5-pyrrolidin-1-ylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1056), -   (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1057), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1058), -   (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1059), -   (R)-4-[5-(1-hydroxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1060), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1061), -   (R)-4-(5-oxo-4,5-dihydro-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1062), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1063), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid ethyl ester (Example 1064), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid (Example 1065), -   (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1066), -   (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1067), -   (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1068), -   (R)-4-(5-cyclobutyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1069), -   (R)-4-[5-(2-methoxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1070), -   (R)-4-[5-(2-methoxy-ethyl)-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1071), -   (R)-4-(5-cyclobutyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1072), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1073), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1074), -   (R)-4-[5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1075), -   (R)-4-[5-(1-methoxymethyl-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1076), -   (R)-4-[5-(1-hydroxymethyl-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1077), -   (R)-4-[5-(2-hydroxy-ethyl)-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1078), -   (R)-4-[5-(1-methoxy-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1079), -   (R)-4-[5-(1-hydroxy-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1080), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-6-carboxylic     acid tert-butyl ester (Example 1081), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-6-carboxylic     acid (Example 1082), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid ethyl ester (Example 1083), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid (Example 1084), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1085), -   (R)-4-(5-oxo-4,5-dihydro-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1086), -   (R)-4-(5-difluoromethoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1087), -   (R)-4-(5-isopropyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1088), -   (R)-4-(5-isopropyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1089), -   (R)-4-(7-amino-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1090), -   (R)-4-[7-amino-5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1091), -   hydroxy-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-acetic     acid (Example 1092), -   4-chloro-2-[(R)-3-[4-(ethyl-methyl-amino)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 1093), -   {5-methyl-3-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrazol-1-yl}-acetic     acid (Example 1094), -   [(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylmethyl]-triethyl-ammonium     trifluoro-methanesulfonate (Example 1095), -   (R)-4-[5-(2-hydroxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1098), -   (R)-1-(4-cyclopropyl-benzenesulfonyl)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1099), -   (R)-1-(4-cyclopropyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1100), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-fluoro-4-trifluoromethoxy-benzylamide (Example 1101), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-fluoro-4-trifluoromethoxy-benzylamide (Example 1102), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid (Example 1104), -   (R)-4-(5-hydroxymethyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1105), -   {4-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-4H-thiazolo[4,5-d]pyridazin-5-yl}-acetic     acid (Example 1106), -   (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1107), -   (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1108), -   2-[(R)-3-(4-difluoromethoxy-3-fluoro-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid (Example 1109), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(2-fluoro-4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1110), -   (R)-3-(4-difluoromethoxy-3-fluoro-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 1111), -   3-{4-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-4H-thiazolo[4,5-d]pyridazin-5-yl}propionic     acid (Example 1112), -   (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1113), and -   (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1114),     or a pharmaceutically acceptable salt thereof, or a solvate thereof.     [33] A pharmaceutical composition comprising a compound of any one     of [15] to [32] or a pharmaceutically acceptable salt thereof, or a     solvate thereof, and a pharmaceutically acceptable carrier.     [34] An antiviral agent comprising a compound of any one of [15] to     [32] or a pharmaceutically acceptable salt thereof, or a solvate     thereof, and a pharmaceutically acceptable carrier.     [35] A therapeutic agent for hepatitis C comprising, as an active     ingredient, a compound of any one of [15] to [32] or a     pharmaceutically acceptable salt thereof, or a solvate thereof.     [36] A therapeutic agent for hepatitis C comprising (a) an HCV     polymerase inhibitor of [14] and (b) at least one pharmaceutical     agent selected from the group consisting of a different antiviral     agent, an antiinflammatory agent and an immunostimulant in     combination.     [37] A therapeutic agent for hepatitis C comprising (a) an HCV     polymerase inhibitor of [14] and (b) interferon in combination.     [38] A pharmaceutical composition comprising (a) a compound of any     one of [15] to [32] or a pharmaceutically acceptable salt thereof,     or a solvate thereof, and (b) at least one pharmaceutical agent     selected from the group consisting of a different antiviral agent,     an antiinflammatory agent and an immunostimulant.     [39] A pharmaceutical composition comprising (a) a compound of any     one of [15] to [32] or a pharmaceutically acceptable salt thereof,     or a solvate thereof, and (b) interferon.     [40] Use of a compound represented by the formula [I] of [1], or a     pharmaceutically acceptable salt thereof, or a solvate thereof, for     the production of an anti-HCV agent.     [41] Use of a compound represented by the formula [I] of [1], or a     pharmaceutically acceptable salt thereof, or a solvate thereof, for     the production of an HCV polymerase inhibitor.     [42] Use of (a) a compound represented by the formula [I] of [1], or     a pharmaceutically acceptable salt thereof, or a solvate thereof,     and (b) at least one pharmaceutical agent selected from the group     consisting of a different antiviral agent, an antiinflammatory agent     and an immunostimulant, for the production of a therapeutic agent     for hepatitis C.     [43] Use of (a) a compound represented by the formula [I] of [1], or     a pharmaceutically acceptable salt thereof, or a solvate thereof,     and (b) interferon, for the production of a therapeutic agent for     hepatitis C.     [44] A method for treating hepatitis C in a mammal, comprising     administering an effective amount of a compound represented by the     formula [I] of [1], or a pharmaceutically acceptable salt thereof,     or a solvate thereof to the mammal.     [45] The method of [44] further comprising administering an     effective amount of at least one pharmaceutical agent selected from     the group consisting of a different antiviral agent, an     antiinflammatory agent and an immunostimulant to the mammal.     [46] The method of [44] further comprising administering an     effective amount of interferon to the mammal.     [47] A method for inhibiting HCV polymerase in a mammal, comprising     administering an effective amount of a compound represented by the     formula [I] of [1], or a pharmaceutically acceptable salt thereof,     or a solvate thereof to the mammal.     [48] The method of [47] further comprising administering an     effective amount of at least one pharmaceutical agent selected from     the group consisting of a different antiviral agent, an     antiinflammatory agent and an immunostimulant to the mammal.     [49] The method of [47] further comprising administering an     effective amount of interferon to the mammal.     [50] A pharmaceutical composition for the treatment of hepatitis C     comprising a compound represented by the formula [I] of [1], or a     pharmaceutically acceptable salt thereof, or a solvate thereof, and     a pharmaceutically acceptable carrier.     [51] A pharmaceutical composition for inhibiting HCV polymerase     comprising a compound represented by the formula [I] of [1], or a     pharmaceutically acceptable salt thereof, or a solvate thereof, and     a pharmaceutically acceptable carrier.

The definition of each substituent and moiety used in the specification is as follows.

The “halogen atom” is fluorine atom, chlorine atom, bromine atom or iodine atom.

The substituent (group A) on ring A or ring B is preferably a fluorine atom, and group B of the “C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B” is preferably a fluorine atom.

The “C₃₋₁₂ carbon ring group” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 12 carbon atoms, specifically, C₆₋₁₂ aryl group, C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkenyl group, a fused carbon ring group wherein two or more rings constituting them are fused and the like.

The “C₆₋₁₂ aryl group” is an aryl group having 6 to 12 carbon atoms and, for example, phenyl group, naphthyl group (e.g., naphthalen-2-yl etc.), azulenyl group, pentalenyl group and the like can be mentioned.

The “C₃₋₁₀ cycloalkyl group” is a cycloalkyl group having 3 to 10 carbon atoms and, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group etc., and bridged carbon rings such as adamantyl group (e.g., adamantan-1-yl etc.), norbornyl group (e.g., norbornan-2-yl) and the like can be mentioned. It is preferably cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctyl group, more preferably cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, further preferably cyclopropyl group or cyclobutyl group, and most preferably cyclopropyl group.

The “C₃₋₁₀ cycloalkenyl group” is a cycloalkenyl group having 3 to 10 carbon atoms and contains at least one, preferably 1 or 2, double bonds. For example, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl group (2,4-cyclohexadien-1-yl group, 2,5-cyclohexadien-1-yl group etc.), cycloheptenyl group, cyclooctenyl group and the like can be mentioned.

As the fused carbon ring group wherein two or more rings constituting the “C₆₋₁₂ aryl group”, “C₃₋₁₀ cycloalkyl group” and “C₃₋₁₀ cycloalkenyl group” are fused, for example, indenyl group, indanyl group (e.g., indan-5-yl etc.), fluorenyl group, dihydronaphthyl group, tetrahydronaphthyl group (e.g., 1,2,3,4-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydronaphthalen-2-yl etc.), perhydronaphthyl group, tetrahydrobenzocycloheptenyl group (e.g., 6,7,8,9-tetrahydro-5H-benzocycloheptenyl etc.) and the like can be mentioned.

The “heterocyclic group” has, as a ring-constituting atom besides carbon atom, 1 to 6 (preferably 1 to 4) hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, wherein the number of atoms constituting the ring is 3 to 14, and includes a saturated or unsaturated, monocyclic or fused ring.

As the “monocyclic heterocyclic group”, specifically, pyridyl group (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrazinyl group (e.g., pyrazin-2-yl etc.), pyrimidinyl group (e.g., pyrimidin-2-yl, pyrimidin-5-yl etc.), pyridazinyl group (e.g., pyridazin-3-yl etc.), triazinyl group, pyrrolyl group, pyrazolyl group (e.g., pyrazol-1-yl, 1H-pyrazol-3-yl, 2H-pyrazol-3-yl, 1H-pyrazol-4-yl etc.), imidazolyl group (e.g., imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl etc.), triazolyl group (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,3,4-triazol-1-yl etc.), tetrazolyl group (e.g., tetrazol-1-yl, tetrazol-2-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl etc.), thienyl group (e.g., thiophen-2-yl, thiophen-3-yl etc.), furyl group (e.g., furan-3-yl etc.), oxazolyl group (e.g., oxazol-2-yl etc.), isoxazolyl group (e.g., isoxazol-5-yl, isoxazol-3-yl etc.), thiazolyl group (e.g., thiazol-2-yl, thiazol-5-yl etc.), isothiazolyl group (e.g., isothiazol-5-yl, isothiazol-3-yl etc.), thiadiazolyl group (e.g., 1,3,4-thiadiazol-2-yl, 5-yl etc.), oxadiazolyl group (e.g., 1,3,4-oxadiazol-2-yl etc.), 2-oxo-1,2-dihydropyridyl group (e.g., 2-oxo-1,2-dihydropyridin-4-yl, 2-oxo-1,2-dihydropyridin-3-yl, 6-oxo-1,6-dihydropyridin-3-yl etc.), 1,2,3,6-tetrahydropyridyl group (e.g., 1,2,3,6-tetrahydropyridin-4-yl etc.), pyrrolinyl group (e.g., 2-pyrrolin-1-yl group, 3-pyrrolin-3-yl etc.), oxopyrrolinyl group (e.g., 2-oxo-3-pyrrolin-1-yl, 2-oxo-3-pyrrolin-3-yl etc.), dioxopyrrolinyl group (e.g., 2,5-dioxo-3-pyrrolin-3-yl etc.), imidazolinyl group (e.g., 2-imidazolin-2-yl etc.), thiazolinyl group (e.g., 2-thiazolin-2-yl etc.), oxothiazolinyl group (e.g., 4-oxo-4,5-dihydrothiazol-2-yl etc.), oxazolinyl group (e.g., 2-oxazolin-2-yl etc.), azetidinyl group (e.g., azetidin-1-yl, azetidin-3-yl etc.), pyrrolidinyl group (e.g., pyrrolidin-1-yl etc.), oxopyrrolidinyl group (e.g., 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl etc.), dioxopyrrolidinyl group (e.g., 2,5-dioxopyrrolidin-3-yl etc.), oxothiadiazolinyl group (e.g., 5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl etc.), oxooxadiazolinyl group (e.g., 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl etc.), imidazolidinyl group, piperidinyl group (e.g., piperidin-1-yl, piperidin-4-yl etc.), oxopiperidinyl group (e.g., 6-oxopiperidin-3-yl group), piperazinyl group (e.g., piperazin-1-yl etc.), morpholinyl group (e.g., morpholin-4-yl etc.), thiomorpholinyl group, tetrahydropyranyl group and the like can be mentioned.

As the “fused heterocyclic group”, specifically, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalyl group (e.g., quinoxalin-2-yl, quinoxalin-6-yl etc.), phthalazinyl group, cinnolinyl group, naphthyridinyl group (e.g., 1,5-naphthyridin-2-yl, 1,6-naphthyridin-2-yl etc.), indolyl group (e.g., 1H-indol-3-yl etc.), benzimidazolyl group (e.g., 1H-benzimidazol-2-yl etc.), indolinyl group, benzofuranyl group, benzothienyl group (e.g., benzothiophen-2-yl etc.), benzoxazolyl group (e.g., benzoxazol-2-yl etc.), benzodioxinyl group, benzothiazolyl group (e.g., benzothiazol-2-yl etc.), tetrahydroquinolyl group (e.g., 1,2,3,4-tetrahydroquinolin-7-yl etc.), dihydrobenzofuranyl group (e.g., 2,3-dihydrobenzofuran-5-yl etc.), dihydrobenzothienyl group, dihydrobenzodioxinyl group (e.g., 2,3-dihydrobenzo[1,4]dioxin-6-yl etc.), indenothiazolyl group (e.g., 8H-indeno[1,2-d]thiazol-2-yl etc.), tetrahydrobenzothiazolyl group (e.g., 4,5,6,7-tetrahydrobenzothiazol-2-yl etc.), indolizinyl group (e.g., indolizin-2-yl etc.) and the like can be mentioned.

The “fused heterocyclic group” includes a group bonded via carbon atom or nitrogen atom of a fused heterocycle represented by the following formula:

For example,

and the like can be mentioned.

The “fused heterocyclic group” is preferably a bicyclic fused ring, and a fused ring of a monocyclic heterocycle and a monocyclic heterocycle is preferable.

The “C₁₋₁₀ alkyl group” is a straight chain or branched chain alkyl group having 1 to 10 carbon atoms and, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, 1-ethylpropyl group, neopentyl group, hexyl group, heptyl group, 1-propylbutyl group, octyl group, nonyl group, decyl group and the like can be mentioned. It is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms.

The “C₁₋₄ alkyl group” is a straight chain or branched chain alkyl group having 1 to 4 carbon atoms and, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group can be mentioned.

The “C₂₋₁₀ alkynyl group” is a straight chain or branched chain alkynyl group having 2 to 10 carbon atoms and, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group, 1-heptynyl group, 1-octynyl group, 3-methylbut-1-yn-1-yl group and the like can be mentioned. It is preferably an alkynyl group having 2 to 6 carbon atoms, more preferably an alkynyl group having 2 to 4 carbon atoms.

The “C₁₋₄ alkylene” is a straight chain or branched chain alkylene having 1 to 4 carbon atoms and, for example, methylene, ethylene, trimethylene, tetramethylene, —CH(CH₃)—, —C(CH₃)₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—, —CH₂—C(CH₃)₂—, —CH(CH₃)—(CH₂)₂—, —CH₂—CH(CH₃)—CH₂—, —(CH₂)₂—CH(CH₃)— and the like can be mentioned.

The “halogeno C₁₋₄ alkyl group” is the above-defined “C₁₋₄ alkyl group” substituted by the above-defined “halogen atom” and, for example, fluoromethyl group, difluoromethyl group, trifluoromethyl group, bromomethyl group, chloromethyl group, 1,2-dichloroethyl group, 2,2-dichloroethyl group, 2,2,2-trifluoroethyl group and the like can be mentioned.

The “hydroxy C₁₋₄ alkyl group” is the above-defined “C₁₋₄ alkyl group” substituted by a hydroxy group and, for example, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group and the like can be mentioned.

The “carboxy C₁₋₄ alkyl group” is the above-defined “C₁₋₄ alkyl group” substituted by a carboxy group and, for example, carboxymethyl group, 1-carboxyethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group and the like can be mentioned.

The “C₆₋₁₂ aryl-C₁₋₄ alkyl group” is an aryl-alkyl group wherein the alkyl moiety is the above-defined “C₁₋₄ alkyl group”, and the aryl moiety is the above-defined “C₆₋₁₂ aryl group” and, for example, benzyl group, 1-phenylethyl group, 2-phenylethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 4-phenylbutyl group and the like can be mentioned.

The “heterocyclyl-C₁₋₄ alkyl group” is a heterocyclyl-alkyl group wherein the alkyl moiety is the above-defined “C₁₋₄ alkyl group” and the heterocyclyl moiety is the above-defined “heterocyclic group” and, for example, pyrrolidinylmethyl group (e.g., pyrrolidin-1-ylmethyl etc.), piperidinylmethyl group (e.g., piperidin-1-ylmethyl, piperidin-4-ylmethyl etc.), piperazinylmethyl group (e.g., piperazin-1-ylmethyl etc.), morpholinylmethyl group (e.g., morpholin-4-ylmethyl etc.), thiomorpholinylmethyl group and the like can be mentioned.

The “C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group” is a cycloalkyl-alkyl group wherein the alkyl moiety is the above-defined “C₁₋₄ alkyl group” and the cycloalkyl moiety is the above-defined “C₃₋₁₀ cycloalkyl group” and, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2-cyclopropylethyl group and the like can be mentioned.

The “C₁₋₄ alkoxy group” is an alkyl-oxy group wherein the alkyl moiety is the above-defined “C₁₋₄ alkyl group” and, for example, methoxy group, ethoxy group, propoxy group, isopropyloxy group, butoxy group, isobutoxy group, tert-butoxy group and the like can be mentioned.

The “C₁₋₄ alkylamino group” is an alkyl-amino group wherein the alkyl moiety is the above-defined “C₁₋₄ alkyl group” and, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group and the like can be mentioned.

The “di(C₁₋₄ alkyl)amino group” is a dialkyl-amino group wherein the alkyl moiety is the above-defined “C₁₋₄ alkyl group” and, for example, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di-sec-butylamino group, di-tert-butylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-butyl-N-methylamino group and the like can be mentioned.

The “C₁₋₄ alkoxy-carbonyl group” is an alkoxy-carbonyl group wherein the alkoxy moiety is the above-defined “C₁₋₄ alkoxy group” and, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropyloxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, tert-butoxycarbonyl group and the like can be mentioned.

The “C₁₋₄ alkylamino-carbonyl group” is an alkylamino-carbonyl group wherein the alkylamino moiety is the above-defined “C₁₋₄ alkylamino group” and, for example, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, isobutylaminocarbonyl group, sec-butylaminocarbonyl group, tert-butylaminocarbonyl, group and the like can be mentioned.

The “di(C₁₋₄ alkyl)amino-carbonyl group” is a dialkylamino-carbonyl group wherein the dialkylamino moiety is the above-defined “di(C₁₋₄ alkyl)amino group” and, for example, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, diisopropylaminocarbonyl group, dibutylaminocarbonyl group, diisobutylaminocarbonyl group, di-sec-butylaminocarbonyl group, di-tert-butylaminocarbonyl group, N-ethyl-N-methylaminocarbonyl group, N-methyl-N-propylaminocarbonyl group, N-butyl-N-methylaminocarbonyl group and the like can be mentioned.

The “heterocyclyl-carbonyl group” is a heterocyclyl-carbonyl group wherein the heterocyclyl moiety is a ring constituting the above-defined “heterocyclic group” and, for example, pyrrolidinylcarbonyl group (e.g., pyrrolidin-1-ylcarbonyl etc.), piperidinylcarbonyl group (e.g., piperidin-1-ylcarbonyl etc.) and morpholinylcarbonyl group (e.g., morpholine-4-carbonyl etc.) can be mentioned.

The “tri(C₁₋₄ alkyl)ammoniumyl group” is a trialkyl-ammoniumyl group (trialkyl-ammonio group) wherein the alkyl moiety is the above-defined “C₁₋₄ alkyl group” and, for example, trimethylammoniumyl group, triethylammoniumyl group, tripropylammoniumyl group, tributylammoniumyl group and the like can be mentioned.

The “C₁₋₄ alkoxy C₁₋₄ alkyl group” is the above-defined “C₁₋₄ alkyl group” substituted by the above-defined “C₁₋₄ alkoxy group” and, for example, methoxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, 3-methoxypropyl group, 4-methoxybutyl group, ethoxymethyl group, 2-ethoxyethyl group and the like can be mentioned.

The “carboxy C₁₋₄ alkoxy group” is the above-defined “C₁₋₄ alkoxy group” substituted by a carboxy group and, for example, carboxymethoxy group, 1-carboxyethoxy group, 2-carboxyethoxy group, 3-carboxypropoxy group, 4-carboxybutoxy group and the like can be mentioned.

The “a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group A” is the above-defined “C₃₋₁₂ carbon ring group” optionally substituted by 1 to 5 substituents, and includes unsubstituted C₃₋₁₂ carbon ring group. The substituent is selected from group A.

Specifically, phenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-propylphenyl group, 4-isopropylphenyl group, 4-butylphenyl group, 4-isobutylphenyl group, 4-tert-butylphenyl group, 4-tert-pentylphenyl group, 4-neopentylphenyl group, 4-(1-ethylpropyl)phenyl group, 4-(1-propylbutyl)phenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 4-(1,1-difluoroethyl)phenyl group, 4-(1,1-difluoropropyl)phenyl group, 4-pentafluoroethylphenyl group, 4-(1-cyano-1-methylethyl)phenyl group, 4-(hydroxymethyl)phenyl group, 4-(2-hydroxyethyl)phenyl group, 4-(3-hydroxypropyl)phenyl group, 4-(2-hydroxy-1,1-dimethylethyl)phenyl group, 4-(methoxymethyl)phenyl group, 4-(2-methoxy-1,1-dimethylethyl)phenyl group, 4-[difluoro(methoxy)methyl]phenyl group, 4-(2-methoxycarbonylethyl)phenyl group, 4-(1-methoxycarbonyl-1-methylethyl)phenyl group, 4-(1-carboxy-1-methylethyl)phenyl group, 4-(1-dimethylcarbamoyl-1-methylethyl)phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-bromophenyl group, 4-bromophenyl group, 4-iodophenyl group, 4-nitrophenyl group, 4-cyanophenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 4-ethoxyphenyl group, 4-propoxyphenyl group, 4-isopropoxyphenyl group, 4-fluoromethoxyphenyl group, 4-difluoromethoxyphenyl group, 3-trifluoromethoxyphenyl group, 4-trifluoromethoxyphenyl group, 4-(2,2,2-trifluoroethoxy)phenyl group, 4-(1,1,2,2-tetrafluoroethoxy)phenyl group, 3-carboxymethoxyphenyl group, 4-carboxymethoxyphenyl group, 4-methoxycarbonylmethoxyphenyl group, 4-(2-methoxycarbonylethoxy)phenyl group, 4-phenoxyphenyl group, 3-ethoxycarbonylmethoxyphenyl group, 4-ethoxycarbonylmethoxyphenyl group, 2-benzyloxyphenyl group, 4-methylsulfanylphenyl group, 4-trifluoromethylsulfanylphenyl group, 4-(4-chlorophenoxy)phenyl group, 4-(pyridin-3-yloxy)phenyl group, 4-aminophenyl group, 2-dimethylaminophenyl group, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group, 4-diethylaminophenyl group, 4-(N-ethyl-N-methylamino)phenyl group, 4-(N-methyl-N-propylamino)phenyl group, 4-[N-(2-hydroxyethyl)-N-methylamino]phenyl group, 4-(N-carboxymethyl-N-methylamino)phenyl group, 4-(N-ethoxycarbonylmethyl-N-methylamino)phenyl group, 4-acetylaminophenyl group, 4-(2,2-dimethylpropionylamino)phenyl group, 2-carboxyphenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 2-methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group, 2-benzyloxycarbonylphenyl group, 4-sulfamoylphenyl group, 4-acetylphenyl group, 4-pentafluorosulfanylphenyl group, 4-cyclopropylphenyl group, 4-cyclohexylphenyl group, 4-(1-hydroxymethylcyclopropyl)phenyl group, 4-(1-methoxymethylcyclopropyl)phenyl group, 4-(4-carboxymethylcyclohexyl)phenyl group, 4-cyclopentylphenyl group, biphenyl-2-yl group, biphenyl-3-yl group, biphenyl-4-yl group, 2′-chlorobiphenyl-4-yl group, 3′-chlorobiphenyl-4-yl group, 4′-chlorobiphenyl-4-yl group, 2′-hydroxybiphenyl-4-yl group, 3′-hydroxybiphenyl-4-yl group, 2′-carboxymethoxybiphenyl-4-yl group, 3′-carboxymethoxybiphenyl-4-yl group, 3′-carboxybiphenyl-4-yl group, 4-(azetidin-1-yl)phenyl group, 4-cyclopropylmethylphenyl group, 4-(pyrrolidin-1-yl)phenyl group, 4-(2-oxopyrrolidin-1-yl)phenyl group, 4-(piperidin-1-yl)phenyl group, 4-(morpholin-4-yl)phenyl group, 4-(4-methylpiperazin-1-yl)phenyl group, 4-(1-methyl-1H-pyrazol-4-yl)phenyl group, 4-(furan-3-yl)phenyl group, 4-(1,2,3-thiadiazol-4-yl)phenyl group, 4-(thiophen-2-yl)phenyl group, 4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl group, 4-ethyl-2-methylphenyl group, 2-methyl-4-propylphenyl group, 4-isopropyl-2-methylphenyl group, 4-cyclopropyl-2-methylphenyl group, 3,4-dichlorophenyl group, 2,4-dichlorophenyl group, 3,5-dichlorophenyl group, 4-bromo-2-chlorophenyl group, 2-chloro-4-propylphenyl group, 2-fluoro-4-isopropylphenyl group, 2,4-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 4-bromo-2-fluorophenyl group, 4-bromo-3-fluorophenyl group, 3-ethyl-4-methoxyphenyl group, 3-isopropyl-4-methoxyphenyl group, 3-tert-butyl-4-methoxyphenyl group, 3-chloro-4-methoxyphenyl group, 2-fluoro-4-trifluoromethoxyphenyl group, 3-fluoro-4-trifluoromethoxyphenyl group, 3-iodo-4-trifluoromethoxyphenyl group, 3-propyl-4-trifluoromethoxyphenyl group, 3-(2-carboxyethyl)-4-trifluoromethoxyphenyl group, 3-(3-carboxypropyl)-4-trifluoromethoxyphenyl group, 3-carboxy-4-methoxyphenyl group, 3-carboxy-4-trifluoromethoxyphenyl group, 4-methoxy-3-methoxycarbonylphenyl group, 4-methoxy-3-methoxycarbonylmethylphenyl group, 4-methoxy-3-(2-methoxycarbonylethyl)phenyl group, 3-carboxymethyl-4-methoxyphenyl group, 3-(2-carboxyethyl)-4-methoxyphenyl group, 3-cyano-4-methoxyphenyl group, 3-cyclopentyl-4-methoxyphenyl group, 4-methoxy-3-(2H-tetrazol-5-yl)phenyl group, 3-hydroxy-4-propylphenyl group, 3-amino-4-propylphenyl group, 3-hydroxy-4-methoxyphenyl group, 4-difluoromethoxy-2-fluorophenyl group, 4-difluoromethoxy-3-fluorophenyl group, 4-carboxy-3-fluorophenyl group, 2-(4-cyanophenoxy)-3,5-dimethylphenyl group, 2,4,6-trichlorophenyl group, 2,3,5,6-tetrafluoro-4-trifluoromethylphenyl group, cyclohexyl group, 1-hydroxycyclohexyl group, 4-carboxycyclohexyl group, 2-phenylcyclopropyl group, 3-phenylcyclobutyl group, adamantan-1-yl group, indan-5-yl group, 5,6,7,8-tetrahydronaphthalen-2-yl group, 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl group, 7-carboxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl group, naphthalen-2-yl group and the like can be mentioned.

The “heterocyclic group optionally substituted by 1 to 5 substituents selected from group A” is the above-defined “heterocyclic group” optionally substituted by 1 to 5 substituents and includes unsubstituted heterocyclic group. The substituent is selected from group A.

Specifically, pyridin-2-yl group, pyridin-3-yl group, pyridin-4-yl group, 6-propylpyridin-3-yl group, 6-isopropylpyridin-3-yl group, 6-trifluoromethylpyridin-3-yl group, 6-dimethylaminopyridin-3-yl group, 6-(azetidin-1-yl)pyridin-3-yl group, 6-(pyrrolidin-1-yl)pyridin-3-yl group, 6-(morpholin-4-yl)pyridin-3-yl group, 5-bromo-6-chloropyridin-3-yl group, 6-methoxy-5-methylpyridin-2-yl group, 2-oxo-1-propyl-1,2-dihydropyridin-4-yl group, 2-oxo-6-propyl-1,2-dihydropyridin-3-yl group, 1-propyl-1,2,3,6-tetrahydropyridin-4-yl group, 5-methylpyrazin-2-yl group, 1H-indol-3-yl group, 1-propyl-1H-pyrazol-4-yl group, 1H-imidazol-4-yl group, 5-phenylthiophen-2-yl group, 5-(pyridin-2-yl)thiophen-2-yl group, 2,2′-bithiophenyl-5-yl group, 4-methyl-2-propylthiazol-5-yl group, 2-(thiophen-2-yl)thiazol-4-yl group, 1-phenylazetidin-3-yl group, piperidin-1-yl group, piperidin-4-yl group, 1-propylpiperidin-4-yl group, 1-tert-butoxycarbonylpiperidin-4-yl group, 1-acetylpiperidin-4-yl group, morpholin-4-yl group, benzoxazol-2-yl group, indolizin-2-yl group, 5-ethylthiophen-2-yl group, 5-propylthiophen-2-yl group, 5-isopropylthiophen-2-yl group, 5-trifluoromethylthiophen-2-yl group, 5-chlorothiophen-2-yl group, 5-bromothiophen-2-yl group, 5-carboxymethylthiophen-2-yl group, 5-(2-carboxyethyl)thiophen-2-yl group, 5-benzenesulfonylthiophen-2-yl group, 5-(4-chlorophenyl)thiophen-2-yl group, 5-(5-trifluoromethylisoxazol-3-yl)thiophen-2-yl group, 5-(4-chloropyrazol-1-yl)thiophen-2-yl group, 2,3-dihydrobenzofuran-5-yl group, benzothiophen-2-yl group, 2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl group, 1-methyl-1,2,3,4-tetrahydroquinolin-7-yl group, 2-propylthiazol-5-yl group, 4-methylthiazol-2-yl group, 4-hydroxymethylthiazol-2-yl group, 5-hydroxymethylthiazol-2-yl group, 4-carboxymethylthiazol-2-yl group, 4-methoxycarbonylmethylthiazol-2-yl group, 4-(2-carboxyethyl)thiazol-2-yl group, 4-carboxythiazol-2-yl group, 5-carboxythiazol-2-yl group, 5-methoxycarbonylthiazol-2-yl group, 4-ethoxycarbonylthiazol-2-yl group, 4-phenylthiazol-2-yl group, 5-carboxy-4-methylthiazol-2-yl group, 4-carboxy-5-methylthiazol-2-yl group, 4-ethyl-5-carboxythiazol-2-yl group, 5-carboxy-4-trifluoromethylthiazol-2-yl group, 5-hydroxymethyl-4-methylthiazol-2-yl group, 5-methoxycarbonyl-4-methylthiazol-2-yl group, 5-tert-butoxycarbonyl-4-methylthiazol-2-yl group, 5-ethoxycarbonyl-4-trifluoromethylthiazol-2-yl group, 5-methylaminomethyl-4-methylthiazol-2-yl group, 5-dimethylaminomethyl-4-methylthiazol-2-yl group, 5-carbamoyl-4-methylthiazol-2-yl group, 5-methylcarbamoyl-4-methylthiazol-2-yl group, 5-dimethylcarbamoyl-4-methylthiazol-2-yl group, 5-carboxymethylcarbamoyl-4-methylthiazol-2-yl group, 5-tert-butoxycarbonylmethylcarbamoyl-4-methylthiazol-2-yl group, 5-(2-tert-butoxycarbonylethyl)carbamoyl-4-methylthiazol-2-yl group, 5-(2-carboxyethyl)carbamoyl-4-methylthiazol-2-yl group, 5-((R)-1-carboxyethyl)carbamoyl-4-methylthiazol-2-yl group, 5-((S)-1-carboxyethyl)carbamoyl-4-methylthiazol-2-yl group, 5-carboxy-4-methoxymethylthiazol-2-yl group, 5-methanesulfonylaminocarbonyl-4-methylthiazol-2-yl group, 5-(2-carboxyethyl)-4-methylthiazol-2-yl group, 5-(carboxy)(hydroxy)methyl-4-methylthiazol-2-yl group, 5-(ethoxycarbonyl)(hydroxy)methyl-4-methylthiazol-2-yl group, 5-cyano-4-methylthiazol-2-yl group, 4-methyl-5-sulfamoylthiazol-2-yl group, 4-methyl-5-methylsulfamoylthiazol-2-yl group, 5-dimethylsulfamoyl-4-methylthiazol-2-yl group, 5-acetylsulfamoyl-4-methylthiazol-2-yl group, 5-acetyl-4-methylthiazol-2-yl group, 5-carboxycarbonyl-4-methylthiazol-2-yl group, 5-ethoxycarbonylcarbonyl-4-methylthiazol-2-yl group, 5-methylcarbamoylcarbonyl-4-methylthiazol-2-yl group, 4-methyl-5-(1H-tetrazol-5-yl)thiazol-2-yl group, 4-methyl-5-(pyrrolidin-1-ylmethyl)thiazol-2-yl group, 4,5-bis(hydroxymethyl)thiazol-2-yl group, 4-carboxy-5-hydroxymethylthiazol-2-yl group, 5-carboxy-4-hydroxymethylthiazol-2-yl group, 4-carboxy-5-methoxymethylthiazol-2-yl group, 5-carboxy-4-chlorothiazol-2-yl group, 4-amino-5-ethoxycarbonylthiazol-2-yl group, pyrazin-2-yl group, 5-cyanopyrazin-2-yl group, 5-hydroxymethylpyrazin-2-yl group, 5-dimethylaminomethylpyrazin-2-yl group, 5-(triethylammoniumylmethyl)pyrazin-2-yl group, 5-methoxycarbonylpyrazin-2-yl group, 5-aminopyrazin-2-yl group, 5-methanesulfonylaminopyrazin-2-yl group, 5-carboxypyrazin-2-yl group, 5-carbamoylpyrazin-2-yl group, 5-ethylcarbamoylpyrazin-2-yl group, 5-tert-butylcarbamoylpyrazin-2-yl group, 5-(1H-tetrazol-5-yl)pyrazin-2-yl group, 5-(pyrrolidin-1-ylmethyl)pyrazin-2-yl group, 5-(morpholin-4-ylmethyl)pyrazin-2-yl group, 5-(4-methylpiperazin-1-ylmethyl)pyrazin-2-yl group, 5-methoxycarbonyl-3-methylpyrazin-2-yl group, 5-carboxy-6-methylpyrazin-2-yl group, 6-amino-5-hydroxymethylpyrazin-2-yl group, 6-amino-5-aminomethylpyrazin-2-yl group, 6-amino-5-carboxypyrazin-2-yl group, 6-amino-5-methoxycarbonylpyrazin-2-yl group, 6-acetylamino-5-methoxycarbonylpyrazin-2-yl group, 3,6-dimethyl-5-carboxypyrazin-2-yl group, 6-bromo-3-chloro-5-methoxycarbonylpyrazin-2-yl group, 6-amino-3-chloro-5-methoxycarbonylpyrazin-2-yl group, 5-aminopyridin-2-yl group, 5-carboxypyridin-2-yl group, 4-carboxypyridin-2-yl group, 5-methoxycarbonylpyridin-2-yl group, 5-tert-butoxycarbonylpyridin-2-yl group, 5-carboxy-6-methylpyridin-2-yl group, 5-carboxy-3-fluoro-6-methylpyridin-2-yl group, 6-carboxypyridin-3-yl group, 6-oxo-1,6-dihydropyridin-3-yl group, 5-carboxypyrimidin-2-yl group, 5-ethoxycarbonyl-4-hydroxypyrimidin-2-yl group, 5-carboxy-4-hydroxypyrimidin-2-yl group, 5-methoxycarbonyl-4-methylpyrimidin-2-yl group, 5-carboxy-4-methylpyrimidin-2-yl group, 5-benzyloxycarbonyl-4-methylpyrimidin-2-yl group, 4-aminopyrimidin-2-yl group, 6-chloropyrimidin-4-yl group, 2-hydroxypyrimidin-4-yl group, 2-aminopyrimidin-4-yl group, 6-aminopyrimidin-4-yl group, 6-hydroxypyridazin-3-yl group, 6-carboxypyridazin-3-yl group, 6-carbamoylpyridazin-3-yl group, 5-methyl-6-hydroxypyridazin-3-yl group, 6-carboxy-5-methylpyridazin-3-yl group, 6-methoxycarbonyl-5-methylpyridazin-3-yl group, 6-carbamoyl-5-methylpyridazin-3-yl group, 1-methyl-1H-pyrazol-3-yl group, 5-methyl-1H-pyrazol-3-yl group, 5-carboxy-1H-pyrazol-3-yl group, 1-carboxymethyl-5-methyl-1H-pyrazol-3-yl group, 5-carboxy-1-methyl-1H-pyrazol-3-yl group, 5-carboxy-2-methyl-2H-pyrazol-3-yl group, 4-chloro-5-carboxy-1H-pyrazol-3-yl group, 1H-imidazol-2-yl group, 1-methyl-1H-imidazol-2-yl group, 4-methyl-5-carboxyoxazol-2-yl group, 1,2,4-triazol-3-yl group, 1,2,4-triazol-4-yl group, 5-bromo-1,2,4-triazol-3-yl group, 5-nitro-1,2,4-triazol-3-yl group, 5-amino-1,2,4-triazol-3-yl group, 3-amino-1,2,4-triazol-1-yl group, 5-amino-3-methyl-1,2,4-triazol-1-yl group, benzothiazol-2-yl group, 4-carboxybenzothiazol-2-yl group, 8H-indeno[1,2-d]thiazol-2-yl group, 2-imidazolin-2-yl group, 2-thiazolin-2-yl group, 4-oxo-4,5-dihydrothiazol-2-yl group, 2-oxazolin-2-yl group, 2,5-dioxopyrrolidin-3-yl group, 4-phenyl-2,5-dioxo-3-pyrrolin-3-yl group, 2-oxopyrrolidin-3-yl group, 3-carboxyazetidin-1-yl group, 4-carboxypiperidin-1-yl group, 6-oxopiperidin-3-yl group, 5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl group, 4,5,6,7-tetrahydrobenzothiazol-2-yl group, 5-methylisoxazol-3-yl group, 1H-imidazol-1-yl group, 1-methyl-1H-imidazol-4-yl group, 1,2,3-triazol-1-yl group, 1,2,4-triazol-1-yl group, 1,3,4-triazol-1-yl group, 1,2,3-triazol-2-yl group, pyrazol-1-yl group, tetrazol-1-yl group, 1H-tetrazol-5-yl group, 2H-tetrazol-5-yl group, tetrazol-2-yl group, 5-methyltetrazol-1-yl group, 5-methyltetrazol-2-yl group, 1-methyltetrazol-5-yl group, 2-methyltetrazol-5-yl group, 5-isopropyltetrazol-1-yl group, 5-isopropyltetrazol-2-yl group, 5-carboxymethyltetrazol-1-yl group, 5-carboxymethyltetrazol-2-yl group, 5-ethoxycarbonylmethyltetrazol-1-yl group, 5-ethoxycarbonylmethyltetrazol-2-yl group, 1-ethoxycarbonylmethyltetrazol-5-yl group, 2-ethoxycarbonylmethyltetrazol-5-yl group, 5-[2-(morpholin-4-yl)-2-oxoethyl]tetrazol-2-yl group, 5-aminotetrazol-1-yl group, 5-aminotetrazol-2-yl group, 5-phenyltetrazol-2-yl group, 3-methylisoxazol-5-yl group, 4-methylpiperazin-1-yl group, 2-trifluoromethylpyridin-4-yl group, 2-hydroxymethylpyridin-4-yl group, 2-carboxypyridin-4-yl group, 2-carbamoylpyridin-4-yl group, 2-dimethylcarbamoylpyridin-4-yl group, 2-(cyclopropylcarbamoyl)pyridin-4-yl group, 2-(morpholine-4-carbonyl)pyridin-4-yl group, 2-(pyrrolidine-1-carbonyl)pyridin-4-yl group, 2-chloropyridin-4-yl group, 2-methoxypyridin-4-yl group, 2-tert-butoxycarbonylpyridin-4-yl group, pyrimidin-4-yl group, thiazol-2-yl group, thiazol-4-yl group, thiazol-5-yl group, 2-methylthiazol-4-yl group, 4-(1-hydroxy-1-methylethyl)thiazol-2-yl group, 4-ethoxycarbonylmethylthiazol-2-yl group, 4-[2-(morpholin-4-yl)-2-oxoethyl]thiazol-2-yl group, 3-methylisothiazol-5-yl group, 1,3,4-thiadiazol-2-yl group, 5-methyl-1,3,4-thiadiazol-2-yl group, 5-bromo-1,3,4-thiadiazol-2-yl group, 5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl group, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl group, 5-hydroxymethyl-1,3,4-thiadiazol-2-yl group, 5-(1-hydroxy-1-methylethyl)-1,3,4-thiadiazol-2-yl group, 5-((R)-3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl group, 5-(4-hydroxypiperidine-1-carbonyl)-1,3,4-thiadiazol-2-yl group, 5-(morpholine-4-carbonyl)-1,3,4-thiadiazol-2-yl group, 5-acetyl-1,3,4-thiadiazol-2-yl group, 1,3,4-oxadiazol-2-yl group, 3-methyl-1,2,4-thiadiazol-5-yl group, 3-methoxy-1,2,4-thiadiazol-5-yl group, 3-acetylamino-1,2,4-thiadiazol-5-yl group, 5-ethoxycarbonyl-1,3,4-oxadiazol-2-yl group, 5-tert-butoxycarbonylthiophen-2-yl group,

-   1H-benzimidazol-2-yl group, -   quinoxalin-2-yl group, -   quinoxalin-6-yl group, -   5-chloroquinoxalin-2-yl group, -   6-chloroquinoxalin-2-yl group, -   8-chloroquinoxalin-2-yl group, -   6-bromoquinoxalin-2-yl group, -   7-bromoquinoxalin-2-yl group, -   5-carboxyquinoxalin-2-yl group, -   6-carboxyquinoxalin-2-yl group, -   7-carboxyquinoxalin-2-yl group, -   8-carboxyquinoxalin-2-yl group, -   6-ethoxycarbonylquinoxalin-2-yl group, -   7-ethoxycarbonylquinoxalin-2-yl group, -   1,5-naphthyridin-2-yl group, -   1,6-naphthyridin-2-yl group, -   thiazolo[5,4-c]pyridin-2-yl group, -   6-carboxy-thiazolo[5,4-c]pyridin-2-yl group, -   7-carboxy-thiazolo[5,4-c]pyridin-2-yl group, -   7-ethoxycarbonyl-thiazolo[5,4-c]pyridin-2-yl group, -   6-tert-butoxycarbonyl-thiazolo[5,4-c]pyridin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[5,4-c]pyridin-2-yl group, -   4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   5-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl     group, -   5-benzyloxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl     group, -   5-ethylcarbamoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl     group, -   5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   5-methanesulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl     group, -   4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   thiazolo[5,4-b]pyridin-2-yl group, -   5-methoxy-thiazolo[5,4-b]pyridin-2-yl group, -   5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl group, -   thiazolo[4,5-b]pyrazin-2-yl group, -   thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-ethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-isopropyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-tert-butyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-hydroxymethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-hydroxyethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(2-hydroxyethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-hydroxy-1-methylethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(2-methoxyethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-ethynyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(3-hydroxy-3-methyl-but-1-ynyl)-thiazolo[4,5-d]pyrimidin-2-yl     group, -   5-fluoro-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-chloro-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-bromo-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-cyano-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-hydroxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methoxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-difluoromethoxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-amino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methylamino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-isopropylamino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-dimethylamino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(2-hydroxyethylamino)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-carboxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-ethoxycarbonyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-carbamoyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methylcarbamoyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-dimethylcarbamoyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(N-methoxy-N-methylcarbamoyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-acetyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-cyclobutyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-hydroxymethylcyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-methoxymethylcyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-hydroxycyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-methoxycyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(pyrrolidin-1-ylmethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-cyclopropylmethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5,7-dichloro-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-bromo-7-diethylamino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5,7-dihydroxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-methoxy-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-chloro-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-(1-hydroxy-1-methylethyl)-thiazolo[4,5-d]pyrimidin-2-yl     group, -   7-amino-5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-carbamoyl-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-chloro-2-diethylamino-thiazolo[4,5-d]pyrimidin-7-yl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   5-methyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   7-oxo-5-trifluoromethyl-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl     group, -   5-chloro-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   thiazolo[5,4-d]pyrimidin-2-yl group, -   5-methyl-thiazolo[5,4-d]pyrimidin-2-yl group, -   thiazolo[4,5-d]pyridazin-2-yl group, -   4-methyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-hydroxymethyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-chloro-thiazolo[4,5-d]pyridazin-2-yl group, -   7-chloro-thiazolo[4,5-d]pyridazin-2-yl group, -   4-methoxy-thiazolo[4,5-d]pyridazin-2-yl group, -   7-methoxy-thiazolo[4,5-d]pyridazin-2-yl group, -   4-carboxy-thiazolo[4,5-d]pyridazin-2-yl group, -   4-ethoxycarbonyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-carbamoyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-methylcarbamoyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-dimethylcarbamoyl-thiazolo[4,5-d]pyridazin-2-yl group, -   7-chloro-4-methyl-thiazolo[4,5-d]pyridazin-2-yl group, -   7-chloro-4-ethoxycarbonyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   5-methyl-4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   5-ethyl-4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   5-(2-hydroxyethyl)-4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   5-(2-methoxyethyl)-4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-methyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   6-methyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-hydroxymethyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   4-carboxy-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-ethoxycarbonyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   4-carbamoyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-methylcarbamoyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl group, -   thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4-methoxy-thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4-amino-thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4-(2-hydroxyethylamino)-thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4-oxo-3,4-dihydrothiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4,6-dioxo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl group, -   1,3-dimethyl-1H-pyrazolo[3,4-d]thiazol-5-yl group, -   7-methyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   5-oxo-7-trifluoromethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   5-isopropyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   5-ethoxycarbonyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   5-methylcarbamoyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   6-chloro-5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl     group, -   4-oxo-3-trifluoromethyl-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl     group, -   [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl group, -   3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl group, -   3-trifluoromethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl     group, -   3H-imidazo[4,5-c]pyridin-2-yl group, -   pteridin-7-yl group, -   pteridin-6-yl group, -   2-methylpteridin-7-yl group, -   2-trifluoromethylpteridin-7-yl group, -   pyrido[3,4-b]pyrazin-2-yl group, -   8-(2-carboxyethyl)-pyrido[3,4-b]pyrazin-2-yl group, -   8-(2-carbamoylethyl)-pyrido[3,4-b]pyrazin-2-yl group, -   8-bromo-pyrido[3,4-b]pyrazin-2-yl group, -   8-cyano-pyrido[3,4-b]pyrazin-2-yl group, -   8-carboxy-pyrido[3,4-b]pyrazin-2-yl group, -   8-carbamoyl-pyrido[3,4-b]pyrazin-2-yl group, -   8-methylcarbamoyl-pyrido[3,4-b]pyrazin-2-yl group, -   8-isopropylcarbamoyl-pyrido[3,4-b]pyrazin-2-yl group, -   8-dimethylcarbamoyl-pyrido[3,4-b]pyrazin-2-yl group, -   pyrido[2,3-b]pyrazin-2-yl group, -   pyrido[2,3-b]pyrazin-3-yl group, -   pyrido[2,3-b]pyrazin-6-yl group, -   pyrazino[2,3-b]pyrazin-2-yl group, -   2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl group, -   2,2-dioxo-1,2,3,4-tetrahydro-2λ⁶-pyrazino[2,3-c][1,2,6]thiadiazin-7-yl     group, -   1H-imidazo[4,5-b]pyrazin-5-yl group, -   2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl group, -   6-hydroxy-[1,2,5]thiadiazolo[3,4-b]pyrazin-5-yl group, -   [1,2,4]triazolo[1,5-a]pyrimidin-5-yl group     and the like can be mentioned.

The “C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B” is the above-defined “C₁₋₁₀ alkyl group” optionally substituted by 1 to 5 substituents and includes an unsubstituted C₁₋₁₀ alkyl group. The substituent is selected from group B.

Specifically, methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, 1-ethylpropyl group, 1-propylbutyl group, tert-pentyl group, neopentyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 1,1-difluoropropyl group, 2,2,2-trifluoroethyl group, 1,1,2,2-tetrafluoroethyl group, pentafluoroethyl group, cyanomethyl group, 1-cyano-1-methylethyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 1-hydroxy-1-methylethyl group, 2-hydroxy-1,1-dimethylethyl group, methoxymethyl group, 2-methoxy-1,1-dimethylethyl group, difluoro(methoxy)methyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl group, dimethylaminomethyl group, dipropylaminomethyl group, 2-dipropylaminoethyl group, carboxymethyl group, 2-carboxyethyl group, (R)-1-carboxyethyl group, (S)-1-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group, 5-carboxypentyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 2-tert-butoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 4-methoxycarbonylbutyl group, 5-ethoxycarbonylpentyl group, 1-methoxycarbonyl-1-methylethyl group, 1-carboxy-1-methylethyl group, carbamoylmethyl group, 2-carbamoylethyl group, 1-dimethylcarbamoyl-1-methylethyl group, 2-acetylaminoethyl group, 2-(morpholin-4-yl)-2-oxoethyl group, triethylammoniumylmethyl group, (carboxy)(hydroxy)methyl group, (ethoxycarbonyl)(hydroxy)methyl group and the like can be mentioned.

The “C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B” is more preferably an unsubstituted alkyl group and a C₁₋₁₀ alkyl group substituted by a halogen atom.

The “C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from group B” is the above-defined “C₂₋₁₀ alkynyl group” optionally substituted by 1 to 5 substituents, and includes an unsubstituted C₂₋₁₀ alkynyl group. The substituent is selected from group B.

Specifically, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 1-hexynyl group, 1-heptynyl group, 1-octynyl group, 3-methylbut-1-yn-1-yl group, 3-hydroxy-3-methylbut-1-yn-1-yl group and the like can be mentioned.

The “C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C” is the above-defined “C₃₋₁₂ carbon ring group” optionally substituted by 1 to 5 substituents, and includes an unsubstituted C₃₋₁₂ carbon ring group. The substituent is selected from group C.

Specifically, phenyl group, 4-chlorophenyl group, 4-cyanophenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 2-carboxymethoxyphenyl group, 3-carboxymethoxyphenyl group, 3-carboxyphenyl group, cyclopropyl group, 1-hydroxymethylcyclopropyl group, 1-methoxymethylcyclopropyl group, 1-hydroxycyclopropyl group, 1-methoxycyclopropyl group, cyclopentyl group, cyclohexyl group and the like can be mentioned.

The “heterocyclic group optionally substituted by 1 to 5 substituents selected from group C” is the above-defined “heterocyclic group” optionally substituted by 1 to 5 substituents, and includes an unsubstituted heterocyclic group. The substituent is selected from group C.

Specifically, azetidin-1-yl group, pyrrolidin-1-yl group, 2-oxopyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, 4-methylpiperazin-1-yl group, 1-methyl-1H-pyrazol-4-yl group, furan-3-yl group, 1,2,3-thiadiazol-4-yl group, thiophen-2-yl group, 1H-tetrazol-5-yl group, 2H-tetrazol-5-yl group, pyridin-2-yl group, pyridin-3-yl group, 5-trifluoromethylisoxazol-3-yl group, 4-chloropyrazol-1-yl group, 3-hydroxypyrrolidin-1-yl group, 4-hydroxypiperidin-1-yl group, 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl group and the like can be mentioned.

The “C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C” is the above-defined “C₆₋₁₂ aryl-C₁₋₄ alkyl group” optionally substituted by 1 to 5 substituents and includes unsubstituted C₆₋₁₂ aryl-C₁₋₄ alkyl group. The substituent is selected from group C. Specifically, benzyl group and the like can be mentioned.

The “heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C” is the above-defined “heterocyclyl-C₁₋₄ alkyl group” optionally substituted by 1 to 5 substituents and includes an unsubstituted heterocyclyl-C₁₋₄ alkyl group. The substituent is selected from group C. Specifically, pyrrolidin-1-ylmethyl group, 4-methylpiperazin-1-ylmethyl group, morpholin-4-ylmethyl group and the like can be mentioned.

The “C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C” is the above-defined “C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group” optionally substituted by 1 to 5 substituents and includes an unsubstituted C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group. The substituent is selected from group C. Specifically, cyclopropylmethyl group and the like can be mentioned.

Preferable groups of ring A, ring B and R are as follows.

Ring A is preferably

-   phenyl group, -   4-methylphenyl group, -   4-ethylphenyl group, -   4-propylphenyl group, -   4-isopropylphenyl group, -   4-butylphenyl group, -   4-tert-butylphenyl group, -   4-tert-pentylphenyl group, -   4-(1-ethylpropyl)phenyl group, -   4-(1-propylbutyl)phenyl group, -   2-trifluoromethylphenyl group, -   3-trifluoromethylphenyl group, -   4-trifluoromethylphenyl group, -   4-(1,1-difluoroethyl)phenyl group, -   4-(1,1-difluoropropyl)phenyl group, -   4-pentafluoroethylphenyl group, -   4-(1-cyano-1-methylethyl)phenyl group, -   4-(hydroxymethyl)phenyl group, -   4-(2-hydroxyethyl)phenyl group, -   4-(3-hydroxypropyl)phenyl group, -   4-(2-hydroxy-1,1-dimethylethyl)phenyl group, -   4-(methoxymethyl)phenyl group, -   4-(2-methoxy-1,1-dimethylethyl)phenyl group, -   4-[difluoro(methoxy)methyl]phenyl group, -   4-(1-methoxycarbonyl-1-methylethyl)phenyl group, -   4-(1-carboxy-1-methylethyl)phenyl group, -   4-(1-dimethylcarbamoyl-1-methylethyl)phenyl group, -   2-fluorophenyl group, -   3-fluorophenyl group, -   2-chlorophenyl group, -   3-chlorophenyl group, -   4-chlorophenyl group, -   4-bromophenyl group, -   4-nitrophenyl group, -   2-hydroxyphenyl group, -   3-hydroxyphenyl group, -   4-hydroxyphenyl group, -   2-methoxyphenyl group, -   3-methoxyphenyl group, -   4-methoxyphenyl group, -   4-ethoxyphenyl group, -   4-isopropoxyphenyl group, -   4-fluoromethoxyphenyl group, -   4-difluoromethoxyphenyl group -   3-trifluoromethoxyphenyl group, -   4-trifluoromethoxyphenyl group, -   4-(2,2,2-trifluoroethoxy)phenyl group, -   4-(1,1,2,2-tetrafluoroethoxy)phenyl group, -   4-phenoxyphenyl group, -   4-methylsulfanylphenyl group, -   4-trifluoromethylsulfanylphenyl group, -   4-aminophenyl group, -   2-dimethylaminophenyl group, -   3-dimethylaminophenyl group, -   4-dimethylaminophenyl group, -   4-diethylaminophenyl group, -   4-(N-ethyl-N-methylamino)phenyl group, -   4-(N-methyl-N-propylamino)phenyl group, -   4-[N-(2-hydroxyethyl)-N-methylamino]phenyl group, -   4-(2,2-dimethylpropionylamino)phenyl group, -   4-carboxyphenyl group, -   4-methoxycarbonylphenyl group, -   4-sulfamoylphenyl group, -   4-pentafluorosulfanylphenyl group, -   4-cyclopropylphenyl group, -   4-(1-hydroxymethylcyclopropyl)phenyl group, -   4-(1-methoxymethylcyclopropyl)phenyl group, -   4-cyclopentylphenyl group, -   biphenyl-2-yl group, -   biphenyl-4-yl group, -   2′-chlorobiphenyl-4-yl group, -   3′-chlorobiphenyl-4-yl group, -   4′-chlorobiphenyl-4-yl group, -   4-(azetidin-1-yl)phenyl group, -   4-(pyrrolidin-1-yl)phenyl group, -   4-(piperidin-1-yl)phenyl group, -   4-(morpholin-4-yl)phenyl group, -   4-(4-methylpiperazin-1-yl)phenyl group, -   4-(1-methyl-1H-pyrazol-4-yl)phenyl group, -   4-(furan-3-yl)phenyl group, -   4-(1,2,3-thiadiazol-4-yl)phenyl group, -   4-(thiophen-2-yl)phenyl group, -   4-ethyl-2-methylphenyl group, -   2-methyl-4-propylphenyl group, -   4-isopropyl-2-methylphenyl group, -   4-cyclopropyl-2-methylphenyl group, -   3,4-dichlorophenyl group, -   2,4-dichlorophenyl group, -   4-bromo-2-chlorophenyl group, -   2-chloro-4-propylphenyl group, -   2-fluoro-4-isopropylphenyl group, -   2,4-dimethoxyphenyl group, -   3,4-dimethoxyphenyl group, -   3-hydroxy-4-propylphenyl group, -   3-amino-4-propylphenyl group, -   3-hydroxy-4-methoxyphenyl group, -   4-difluoromethoxy-2-fluorophenyl group, -   4-difluoromethoxy-3-fluorophenyl group, -   3-fluoro-4-trifluoromethoxyphenyl group, -   2,4,6-trichlorophenyl group, -   2,3,5,6-tetrafluoro-4-trifluoromethylphenyl group, -   cyclohexyl group, -   1-hydroxycyclohexyl group, -   4-carboxycyclohexyl group, -   2-phenylcyclopropyl group, -   3-phenylcyclobutyl group, -   adamantan-1-yl group, -   naphthalen-2-yl group, -   pyridin-2-yl group, -   pyridin-3-yl group, -   pyridin-4-yl group, -   6-propylpyridin-3-yl group, -   6-isopropylpyridin-3-yl group, -   6-trifluoromethylpyridin-3-yl group, -   6-dimethylaminopyridin-3-yl group, -   6-(azetidin-1-yl)pyridin-3-yl group, -   6-(pyrrolidin-1-yl)pyridin-3-yl group, -   6-methoxy-5-methylpyridin-2-yl group, -   2-oxo-1-propyl-1,2-dihydropyridin-4-yl group, -   2-oxo-6-propyl-1,2-dihydropyridin-3-yl group, -   1-propyl-1,2,3,6-tetrahydropyridin-4-yl group, -   5-methylpyrazin-2-yl group, -   1H-indol-3-yl group, -   1-propyl-1H-pyrazol-4-yl group, -   1H-imidazol-4-yl group, -   5-propylthiophen-2-yl group, -   5-phenylthiophen-2-yl group, -   5-(pyridin-2-yl)thiophen-2-yl group, -   2,2′-bithiophenyl-5-yl group, -   4-methyl-2-propylthiazol-5-yl group, -   2-(thiophen-2-yl)thiazol-4-yl group, -   1-phenylazetidin-3-yl group, -   piperidin-1-yl group, -   piperidin-4-yl group, -   1-propylpiperidin-4-yl group, -   1-tert-butoxycarbonylpiperidin-4-yl group, -   1-acetylpiperidin-4-yl group, -   morpholin-4-yl group, -   benzoxazol-2-yl group, -   indolizin-2-yl     or the like.

Another preferable embodiment of ring A is a phenyl group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, more preferably a phenyl group substituted by 1 to 5 substituents selected from the above-mentioned group A.

In this case, a preferable substituent on the phenyl group is the above-defined “halogen atom”, —OR^(a1) (wherein R^(a1) is as defined above) and the above-defined “C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B”.

The substitution position of the substituent on the phenyl group is preferably monosubstituted at 4-position, 2,4-disubstituted or 3,4-disubstituted, and the substituents at the 2-position, the 3-position and the 4-position may be the same or different. More preferred are monosubstituted at 4-position and 3,4-disubstituted.

n is preferably 1.

Ring B is preferably

-   phenyl group, -   4-methylphenyl group, -   4-ethylphenyl group, -   4-propylphenyl group, -   4-isopropylphenyl group, -   4-butylphenyl group, -   4-isobutylphenyl group, -   4-tert-butylphenyl group, -   4-tert-pentylphenyl group, -   4-neopentylphenyl group, -   4-(1-ethylpropyl)phenyl group, -   3-trifluoromethylphenyl group, -   4-trifluoromethylphenyl group, -   4-hydroxymethylphenyl group, -   4-methoxymethylphenyl group, -   4-(2-methoxycarbonylethyl)phenyl group, -   4-fluorophenyl group, -   2-chlorophenyl group, -   3-chlorophenyl group, -   4-chlorophenyl group, -   3-bromophenyl group, -   4-bromophenyl group, -   4-iodophenyl group, -   4-nitrophenyl group, -   4-cyanophenyl group, -   4-hydroxyphenyl group, -   3-methoxyphenyl group, -   4-methoxyphenyl group, -   4-ethoxyphenyl group, -   4-propoxyphenyl group, -   4-isopropoxyphenyl group, -   4-difluoromethoxyphenyl group, -   4-trifluoromethoxyphenyl group, -   4-(2,2,2-trifluoroethoxy)phenyl group, -   4-(1,1,2,2-tetrafluoroethoxy)phenyl group, -   4-carboxymethoxyphenyl group, -   4-methoxycarbonylmethoxyphenyl group, -   4-(2-methoxycarbonylethoxy)phenyl group, -   4-(4-chlorophenoxy)phenyl group, -   4-(pyridin-3-yloxy)phenyl group, -   4-aminophenyl group, -   4-dimethylaminophenyl group, -   4-(N-carboxymethyl-N-methylamino)phenyl group, -   4-(N-ethoxycarbonylmethyl-N-methylamino)phenyl group, -   4-acetylaminophenyl group, -   3-carboxyphenyl group, -   4-carboxyphenyl group, -   4-methoxycarbonylphenyl group, -   4-acetylphenyl group, -   4-cyclopropylphenyl group, -   4-cyclohexylphenyl group, -   4-(4-carboxymethylcyclohexyl)phenyl group, -   biphenyl-3-yl group, -   biphenyl-4-yl group, -   4′-chlorobiphenyl-4-yl group, -   2′-hydroxybiphenyl-4-yl group, -   3′-hydroxybiphenyl-4-yl group, -   2′-carboxymethoxybiphenyl-4-yl group, -   3′-carboxymethoxybiphenyl-4-yl group, -   3′-carboxybiphenyl-4-yl group, -   4-cyclopropylmethylphenyl group, -   4-(pyrrolidin-1-yl)phenyl group, -   4-(2-oxopyrrolidin-1-yl)phenyl group, -   4-(morpholin-4-yl)phenyl group, -   4-(thiophen-2-yl)phenyl group, -   4-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl group, -   3,4-dichlorophenyl group, -   2,4-dichlorophenyl group, -   3,5-dichlorophenyl group, -   4-bromo-2-fluorophenyl group, -   4-bromo-3-fluorophenyl group, -   3,4-dimethoxyphenyl group, -   3-ethyl-4-methoxyphenyl group, -   3-isopropyl-4-methoxyphenyl group, -   3-tert-butyl-4-methoxyphenyl group, -   3-chloro-4-methoxyphenyl group, -   2-fluoro-4-trifluoromethoxyphenyl group, -   3-fluoro-4-trifluoromethoxyphenyl group, -   3-iodo-4-trifluoromethoxyphenyl group, -   3-propyl-4-trifluoromethoxyphenyl group, -   3-(2-carboxyethyl)-4-trifluoromethoxyphenyl group, -   3-(3-carboxypropyl)-4-trifluoromethoxyphenyl group, -   3-carboxy-4-methoxyphenyl group, -   3-carboxy-4-trifluoromethoxyphenyl group, -   4-methoxy-3-methoxycarbonylphenyl group, -   4-methoxy-3-methoxycarbonylmethylphenyl group, -   4-methoxy-3-(2-methoxycarbonylethyl)phenyl group, -   3-carboxymethyl-4-methoxyphenyl group, -   3-(2-carboxyethyl)-4-methoxyphenyl group, -   3-cyano-4-methoxyphenyl group, -   3-cyclopentyl-4-methoxyphenyl group, -   4-methoxy-3-(2H-tetrazol-5-yl)phenyl group, -   4-carboxy-3-fluorophenyl group, -   2-(4-cyanophenoxy)-3,5-dimethylphenyl group, -   cyclohexyl group, -   indan-5-yl group, -   5,6,7,8-tetrahydronaphthalen-2-yl group, -   6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl group, -   7-carboxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl group, -   naphthalen-2-yl group, -   5-ethylthiophen-2-yl group, -   5-propylthiophen-2-yl group, -   5-isopropylthiophen-2-yl group, -   5-trifluoromethylthiophen-2-yl group, -   5-chlorothiophen-2-yl group, -   5-bromothiophen-2-yl group, -   5-carboxymethylthiophen-2-yl group, -   5-(2-carboxyethyl)thiophen-2-yl group, -   5-benzenesulfonylthiophen-2-yl group, -   5-(4-chlorophenyl)thiophen-2-yl group, -   5-(5-trifluoromethylisoxazol-3-yl)thiophen-2-yl group, -   5-(4-chloropyrazol-1-yl)thiophen-2-yl group, -   6-(morpholin-4-yl)pyridin-3-yl group, -   5-bromo-6-chloropyridin-3-yl group, -   2,3-dihydrobenzofuran-5-yl group, -   benzothiophen-2-yl group, -   2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl group, -   1-methyl-1,2,3,4-tetrahydroquinolin-7-yl group, -   2-propylthiazol-5-yl group     or the like.

Another preferable embodiment of ring B is a phenyl group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, more preferably a phenyl group substituted by 1 to 5 substituents selected from the above-mentioned group A.

In this case, the substituent on the phenyl group is preferably the above-defined “halogen atom”, —OR^(a1) (wherein R^(a1) is as defined above), the above-defined “C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B” or “C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group A” (particularly preferably the above-defined “C₃₋₁₀ cycloalkyl group”).

The substitution position of the substituent on the phenyl group is preferably monosubstituted at 4-position, 2,4 disubstituted or 3,4-disubstituted, wherein the substituents at the 2-position, the 3-position and the 4-position may be the same or different. It is more preferably monosubstituted at 4-position.

R is preferably

-   hydrogen atom, -   formyl group, -   acetyl group, -   propionyl group, -   isobutyryl group, -   2,2-dimethylpropionyl group, -   2-cyanoacetyl group, -   2-hydroxyacetyl group, -   2-hydroxy-2-methylpropionyl group, -   3-hydroxypropionyl group, -   2-methoxyacetyl group, -   2-aminoacetyl group, -   3-aminopropionyl group, -   2-dimethylaminoacetyl group, -   2-dipropylaminoacetyl group, -   3-dipropylaminopropionyl group, -   2-carboxyacetyl group, -   3-carboxypropionyl group -   4-carboxybutyryl group, -   5-carboxypentanoyl group, -   6-carboxyhexanoyl group, -   3-methoxycarbonylpropionyl group, -   4-methoxycarbonylbutyryl group, -   5-methoxycarbonylpentanoyl group, -   6-ethoxycarbonylhexanoyl group, -   methoxycarbonyl group, -   tert-butoxycarbonyl group, -   carbamoyl group, -   ethylcarbamoyl group, -   dimethylcarbamoyl group, -   carboxymethylcarbamoyl group, -   (3-carboxypropyl)carbamoyl group, -   methanesulfonyl group, -   carboxycarbonyl group, -   2-ethoxy-2-oxoacetyl group, -   (Z)-3-carboxyprop-2-enoyl group, -   (E)-3-carboxyprop-2-enoyl group, -   2-carboxymethylaminoacetyl group, -   2-(2-carboxyethylamino)acetyl group, -   acetylaminoacetyl group, -   3-acetylaminopropionyl group, -   2-(3-carboxypropionylamino)acetyl group, -   2-(tert-butoxycarbonylamino)acetyl group, -   3-(tert-butoxycarbonylamino)propionyl group, -   2-(3-methoxycarbonylpropionylamino)acetyl group, -   2-amino-2-oxoacetyl group, -   carbamimidoyl group, -   thiocarbamoyl group, -   methyl group, -   carboxymethyl group, -   methoxycarbonylmethyl group, -   carbamoylmethyl group, -   4-carboxyphenyl group, -   4-methylthiazol-2-yl group, -   4-hydroxymethylthiazol-2-yl group, -   5-hydroxymethylthiazol-2-yl group, -   4-carboxymethylthiazol-2-yl group, -   4-methoxycarbonylmethylthiazol-2-yl group, -   4-(2-carboxyethyl)thiazol-2-yl group, -   4-carboxythiazol-2-yl group, -   5-carboxythiazol-2-yl group, -   5-methoxycarbonylthiazol-2-yl group, -   4-ethoxycarbonylthiazol-2-yl group, -   4-phenylthiazol-2-yl group, -   5-carboxy-4-methylthiazol-2-yl group, -   4-carboxy-5-methylthiazol-2-yl group, -   4-ethyl-5-carboxythiazol-2-yl group, -   5-carboxy-4-trifluoromethylthiazol-2-yl group, -   5-hydroxymethyl-4-methylthiazol-2-yl group, -   5-methoxycarbonyl-4-methylthiazol-2-yl group, -   5-tert-butoxycarbonyl-4-methylthiazol-2-yl group, -   5-ethoxycarbonyl-4-trifluoromethylthiazol-2-yl group, -   5-methylaminomethyl-4-methylthiazol-2-yl group, -   5-dimethylaminomethyl-4-methylthiazol-2-yl group, -   5-carbamoyl-4-methylthiazol-2-yl group, -   5-methylcarbamoyl-4-methylthiazol-2-yl group, -   5-dimethylcarbamoyl-4-methylthiazol-2-yl group, -   5-carboxymethylcarbamoyl-4-methylthiazol-2-yl group, -   5-tert-butoxycarbonylmethylcarbamoyl-4-methylthiazol-2-yl group, -   5-(2-tert-butoxycarbonylethyl)carbamoyl-4-methylthiazol-2-yl group, -   5-(2-carboxyethyl)carbamoyl-4-methylthiazol-2-yl group, -   5-((R)-1-carboxyethyl)carbamoyl-4-methylthiazol-2-yl group, -   5-((S)-1-carboxyethyl)carbamoyl-4-methylthiazol-2-yl group, -   5-carboxy-4-methoxymethylthiazol-2-yl group, -   5-methanesulfonylaminocarbonyl-4-methylthiazol-2-yl group, -   5-(2-carboxyethyl)-4-methylthiazol-2-yl group, -   5-(carboxy)(hydroxy)methyl-4-methylthiazol-2-yl group, -   5-(ethoxycarbonyl)(hydroxy)methyl-4-methylthiazol-2-yl group, -   5-cyano-4-methylthiazol-2-yl group, -   4-methyl-5-sulfamoylthiazol-2-yl group, -   4-methyl-5-methylsulfamoylthiazol-2-yl group, -   5-dimethylsulfamoyl-4-methylthiazol-2-yl group, -   5-acetylsulfamoyl-4-methylthiazol-2-yl group, -   5-acetyl-4-methylthiazol-2-yl group, -   5-carboxycarbonyl-4-methylthiazol-2-yl group, -   5-ethoxycarbonylcarbonyl-4-methylthiazol-2-yl group, -   5-methylcarbamoylcarbonyl-4-methylthiazol-2-yl group, -   4-methyl-5-(1H-tetrazol-5-yl)thiazol-2-yl group, -   4-methyl-5-(pyrrolidin-1-ylmethyl)thiazol-2-yl group, -   4,5-bis(hydroxymethyl)thiazol-2-yl group, -   4-carboxy-5-hydroxymethylthiazol-2-yl group, -   5-carboxy-4-hydroxymethylthiazol-2-yl group, -   4-carboxy-5-methoxymethylthiazol-2-yl group, -   5-carboxy-4-chlorothiazol-2-yl group, -   4-amino-5-ethoxycarbonylthiazol-2-yl group, -   pyrazin-2-yl group, -   5-cyanopyrazin-2-yl group, -   5-hydroxymethylpyrazin-2-yl group, -   5-dimethylaminomethylpyrazin-2-yl group, -   5-(triethylammoniumylmethyl)pyrazin-2-yl group, -   5-methoxycarbonylpyrazin-2-yl group, -   5-aminopyrazin-2-yl group, -   5-methanesulfonylaminopyrazin-2-yl group, -   5-carboxypyrazin-2-yl group, -   5-carbamoylpyrazin-2-yl group, -   5-ethylcarbamoylpyrazin-2-yl group, -   5-tert-butylcarbamoylpyrazin-2-yl group, -   5-(1H-tetrazol-5-yl)pyrazin-2-yl group, -   5-(pyrrolidin-1-ylmethyl)pyrazin-2-yl group, -   5-(morpholin-4-ylmethyl)pyrazin-2-yl group, -   5-(4-methylpiperazin-1-ylmethyl)pyrazin-2-yl group, -   5-methoxycarbonyl-3-methylpyrazin-2-yl group, -   5-carboxy-6-methylpyrazin-2-yl group, -   6-amino-5-hydroxymethylpyrazin-2-yl group, -   6-amino-5-aminomethylpyrazin-2-yl group, -   6-amino-5-carboxypyrazin-2-yl group, -   6-amino-5-methoxycarbonylpyrazin-2-yl group, -   6-acetylamino-5-methoxycarbonylpyrazin-2-yl group, -   3,6-dimethyl-5-carboxypyrazin-2-yl group, -   6-bromo-3-chloro-5-methoxycarbonylpyrazin-2-yl group, -   6-amino-3-chloro-5-methoxycarbonylpyrazin-2-yl group, -   5-aminopyridin-2-yl group, -   5-carboxypyridin-2-yl group, -   4-carboxypyridin-2-yl group, -   5-methoxycarbonylpyridin-2-yl group, -   5-tert-butoxycarbonylpyridin-2-yl group, -   5-carboxy-6-methylpyridin-2-yl group, -   5-carboxy-3-fluoro-6-methylpyridin-2-yl group, -   6-carboxypyridin-3-yl group, -   6-oxo-1,6-dihydropyridin-3-yl group, -   5-carboxypyrimidin-2-yl group, -   5-ethoxycarbonyl-4-hydroxypyrimidin-2-yl group, -   5-carboxy-4-hydroxypyrimidin-2-yl group, -   5-methoxycarbonyl-4-methylpyrimidin-2-yl group, -   5-carboxy-4-methylpyrimidin-2-yl group, -   5-benzyloxycarbonyl-4-methylpyrimidin-2-yl group, -   4-aminopyrimidin-2-yl group, -   pyrimidin-4-yl group, -   6-chloropyrimidin-4-yl group, -   2-hydroxypyrimidin-4-yl group, -   2-aminopyrimidin-4-yl group, -   6-aminopyrimidin-4-yl group, -   6-hydroxypyridazin-3-yl group, -   6-carboxypyridazin-3-yl group, -   6-carbamoylpyridazin-3-yl group, -   5-methyl-6-hydroxypyridazin-3-yl group, -   6-carboxy-5-methylpyridazin-3-yl group, -   6-methoxycarbonyl-5-methylpyridazin-3-yl group, -   6-carbamoyl-5-methylpyridazin-3-yl group, -   5-methyl-1H-pyrazol-3-yl group, -   5-carboxy-1H-pyrazol-3-yl group, -   1-carboxymethyl-5-methyl-1H-pyrazol-3-yl group, -   5-carboxy-1-methyl-1H-pyrazol-3-yl group, -   5-carboxy-2-methyl-2H-pyrazol-3-yl group, -   4-chloro-5-carboxy-1H-pyrazol-3-yl group, -   1H-imidazol-2-yl group, -   1-methyl-1H-imidazol-2-yl group, -   4-methyl-5-carboxyoxazol-2-yl group, -   1,2,4-triazol-3-yl group, -   5-bromo-1,2,4-triazol-3-yl group, -   5-nitro-1,2,4-triazol-3-yl group, -   5-amino-1,2,4-triazol-3-yl group, -   3-methyl-1,2,4-thiadiazol-5-yl group, -   3-methoxy-1,2,4-thiadiazol-5-yl group, -   3-acetylamino-1,2,4-thiadiazol-5-yl group, -   5-tert-butoxycarbonylthiophen-2-yl group, -   benzothiazol-2-yl group, -   4-carboxybenzothiazol-2-yl group, -   8H-indeno[1,2-d]thiazol-2-yl group, -   2-imidazolin-2-yl group, -   2-thiazolin-2-yl group, -   4-oxo-4,5-dihydrothiazol-2-yl group, -   2-oxazolin-2-yl group, -   2,5-dioxopyrrolidin-3-yl group, -   4-phenyl-2,5-dioxo-3-pyrrolin-3-yl group, -   2-oxopyrrolidin-3-yl group, -   6-oxopiperidin-3-yl group, -   5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl group, -   4,5,6,7-tetrahydrobenzothiazol-2-yl group, -   1H-benzimidazol-2-yl group, -   quinoxalin-2-yl group, -   quinoxalin-6-yl group, -   5-chloroquinoxalin-2-yl group, -   6-chloroquinoxalin-2-yl group, -   8-chloroquinoxalin-2-yl group, -   6-bromoquinoxalin-2-yl group, -   7-bromoquinoxalin-2-yl group, -   5-carboxyquinoxalin-2-yl group, -   6-carboxyquinoxalin-2-yl group, -   7-carboxyquinoxalin-2-yl group, -   8-carboxyquinoxalin-2-yl group, -   6-ethoxycarbonylquinoxalin-2-yl group, -   7-ethoxycarbonylquinoxalin-2-yl group, -   1,5-naphthyridin-2-yl group, -   1,6-naphthyridin-2-yl group, -   thiazolo[5,4-c]pyridin-2-yl group, -   6-carboxy-thiazolo[5,4-c]pyridin-2-yl group, -   7-carboxy-thiazolo[5,4-c]pyridin-2-yl group, -   7-ethoxycarbonyl-thiazolo[5,4-c]pyridin-2-yl group, -   6-tert-butoxycarbonyl-thiazolo[5,4-c]pyridin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[5,4-c]pyridin-2-yl group, -   4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   5-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl     group, -   5-benzyloxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl     group, -   5-ethylcarbamoyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl     group, -   5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   5-methanesulfonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl     group, -   4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   thiazolo[5,4-b]pyridin-2-yl group, -   5-methoxy-thiazolo[5,4-b]pyridin-2-yl group, -   5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl group, -   thiazolo[4,5-b]pyrazin-2-yl group, -   thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-ethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-isopropyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-tert-butyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-hydroxymethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-hydroxyethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(2-hydroxyethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-hydroxy-1-methylethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(2-methoxyethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-ethynyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(3-hydroxy-3-methyl-but-1-ynyl)-thiazolo[4,5-d]pyrimidin-2-yl     group, -   5-fluoro-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-chloro-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-bromo-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-cyano-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-hydroxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methoxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-difluoromethoxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-amino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methylamino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-isopropylamino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-dimethylamino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(2-hydroxyethylamino)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-carboxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-ethoxycarbonyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-carbamoyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-methylcarbamoyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-dimethylcarbamoyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(N-methoxy-N-methylcarbamoyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-acetyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-cyclobutyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-hydroxymethylcyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-methoxymethylcyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-hydroxycyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(1-methoxycyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-(pyrrolidin-1-ylmethyl)-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-cyclopropylmethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5,7-dichloro-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-bromo-7-diethylamino-thiazolo[4,5-d]pyrimidin-2-yl group, -   5,7-dihydroxy-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-methoxy-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-chloro-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-(1-hydroxy-1-methylethyl)-thiazolo[4,5-d]pyrimidin-2-yl     group, -   7-amino-5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-amino-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   7-carbamoyl-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl group, -   5-chloro-2-diethylamino-thiazolo[4,5-d]pyrimidin-7-yl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   5-methyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   7-oxo-5-trifluoromethyl-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl     group, -   5-chloro-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   thiazolo[5,4-d]pyrimidin-2-yl group, -   5-methyl-thiazolo[5,4-d]pyrimidin-2-yl group, -   thiazolo[4,5-d]pyridazin-2-yl group, -   4-methyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-hydroxymethyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-chloro-thiazolo[4,5-d]pyridazin-2-yl group, -   7-chloro-thiazolo[4,5-d]pyridazin-2-yl group, -   4-methoxy-thiazolo[4,5-d]pyridazin-2-yl group, -   7-methoxy-thiazolo[4,5-d]pyridazin-2-yl group, -   4-carboxy-thiazolo[4,5-d]pyridazin-2-yl group, -   4-ethoxycarbonyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-carbamoyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-methylcarbamoyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-dimethylcarbamoyl-thiazolo[4,5-d]pyridazin-2-yl group, -   7-chloro-4-methyl-thiazolo[4,5-d]pyridazin-2-yl group, -   7-chloro-4-ethoxycarbonyl-thiazolo[4,5-d]pyridazin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   5-methyl-4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   5-ethyl-4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   5-(2-hydroxyethyl)-4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   5-(2-methoxyethyl)-4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-methyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   6-methyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-hydroxymethyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   4-carboxy-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-ethoxycarbonyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   4-carbamoyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-methylcarbamoyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl     group, -   4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl group, -   thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4-methoxy-thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4-amino-thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4-(2-hydroxyethylamino)-thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4-oxo-3,4-dihydrothiazolo[4,5-d][1,2,3]triazin-6-yl group, -   4,6-dioxo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl group, -   1,3-dimethyl-1H-pyrazolo[3,4-d]thiazol-5-yl group, -   7-methyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   5-oxo-7-trifluoromethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   5-isopropyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   5-ethoxycarbonyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   5-methylcarbamoyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   6-chloro-5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl     group, -   3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl     group, -   4-oxo-3-trifluoromethyl-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl     group, -   [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl group, -   3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl group, -   3-trifluoromethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl     group, -   3H-imidazo[4,5-c]pyridin-2-yl group, -   pteridin-7-yl group, -   pteridin-6-yl group, -   2-methylpteridin-7-yl group, -   2-trifluoromethylpteridin-7-yl group, -   pyrido[3,4-b]pyrazin-2-yl group, -   8-(2-carboxyethyl)-pyrido[3,4-b]pyrazin-2-yl group, -   8-(2-carbamoylethyl)-pyrido[3,4-b]pyrazin-2-yl group, -   8-bromo-pyrido[3,4-b]pyrazin-2-yl group, -   8-cyano-pyrido[3,4-b]pyrazin-2-yl group, -   8-carboxy-pyrido[3,4-b]pyrazin-2-yl group, -   8-carbamoyl-pyrido[3,4-b]pyrazin-2-yl group, -   8-methylcarbamoyl-pyrido[3,4-b]pyrazin-2-yl group, -   8-isopropylcarbamoyl-pyrido[3,4-b]pyrazin-2-yl group, -   8-dimethylcarbamoyl-pyrido[3,4-b]pyrazin-2-yl group, -   pyrido[2,3-b]pyrazin-2-yl group, -   pyrido[2,3-b]pyrazin-3-yl group, -   pyrido[2,3-b]pyrazin-6-yl group, -   pyrazino[2,3-b]pyrazin-2-yl group, -   2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl group, -   2,2-dioxo-1,2,3,4-tetrahydro-2λ⁶-pyrazino[2,3-c][1,2,6]thiadiazin-7-yl     group, -   1H-imidazo[4,5-b]pyrazin-5-yl group, -   2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl group, -   6-hydroxy-[1,2,5]thiadiazolo[3,4-b]pyrazin-5-yl group, -   [1,2,4]triazolo[1,5-a]pyrimidin-5-yl group, -   2-(pyridin-4-yl)ethyl group, -   benzoyl group, -   cyclopropylcarbonyl group, -   pyridine-4-carbonyl group -   triazole-4-carbonyl group, -   5-methylisoxazole-3-carbonyl group, -   3-amino-1,2,4-triazole-1-carbonyl group, -   5-amino-3-methyl-1,2,4-triazole-1-carbonyl group, -   3-carboxyazetidin-1-ylcarbonyl group, -   4-carboxypiperidin-1-ylcarbonyl group, -   phenylacetyl group, -   2-(2-methoxyphenyl)acetyl group, -   2-(3-methoxyphenyl)acetyl group, -   2-(4-methoxyphenyl)acetyl group, -   2-(pyridin-2-yl)acetyl group, -   2-(pyridin-3-yl)acetyl group, -   2-(pyridin-4-yl)acetyl group, -   2-(pyrimidin-4-yl)acetyl group, -   2-(1H-imidazol-1-yl)acetyl group, -   2-(1H-imidazol-4-yl)acetyl group, -   2-(1-methyl-1H-imidazol-4-yl)acetyl group, -   2-(1,2,3-triazol-1-yl)acetyl group, -   2-(1,2,4-triazol-1-yl)acetyl group, -   2-(1,3,4-triazol-1-yl)acetyl group, -   2-(1,2,3-triazol-2-yl)acetyl group, -   2-(pyrazol-1-yl)acetyl group, -   2-(tetrazol-1-yl)acetyl group, -   2-(1H-tetrazol-5-yl)acetyl group, -   2-(tetrazol-2-yl)acetyl group, -   2-(5-methyltetrazol-1-yl)acetyl group, -   2-(5-methyltetrazol-2-yl)acetyl group, -   2-(1-methyltetrazol-5-yl)acetyl group, -   2-(2-methyltetrazol-5-yl)acetyl group, -   2-(5-isopropyltetrazol-1-yl)acetyl group, -   2-(5-isopropyltetrazol-2-yl)acetyl group, -   2-(5-carboxymethyltetrazol-1-yl)acetyl group, -   2-(5-carboxymethyltetrazol-2-yl)acetyl group, -   2-(5-ethoxycarbonylmethyltetrazol-1-yl)acetyl group, -   2-(5-ethoxycarbonylmethyltetrazol-2-yl)acetyl group, -   2-(1-ethoxycarbonylmethyltetrazol-5-yl)acetyl group, -   2-(2-ethoxycarbonylmethyltetrazol-5-yl)acetyl group, -   2-[5-[2-(morpholin-4-yl)-2-oxoethyl]tetrazol-2-yl]acetyl group, -   2-(5-aminotetrazol-1-yl)acetyl group, -   2-(5-aminotetrazol-2-yl)acetyl group, -   2-(5-phenyltetrazol-2-yl)acetyl group, -   2-(3-methylisoxazol-5-yl)acetyl group, -   2-(4-methylpiperazin-1-yl)acetyl group, -   2-(pyrrolidin-1-yl)acetyl group, -   2-(piperidin-1-yl)acetyl group, -   2-(morpholin-4-yl)acetyl group, -   3-(morpholin-4-yl)propionyl group, -   2-cyclohexylacetyl group, -   phenylcarbamoyl group, -   2-chlorophenylcarbamoyl group, -   3-chlorophenylcarbamoyl group, -   4-chlorophenylcarbamoyl group, -   2-hydroxyphenylcarbamoyl group, -   2-methoxyphenylcarbamoyl group, -   3-methoxyphenylcarbamoyl group, -   4-methoxyphenylcarbamoyl group, -   2-benzyloxyphenylcarbamoyl group, -   2-carboxyphenylcarbamoyl group, -   3-carboxyphenylcarbamoyl group, -   4-carboxyphenylcarbamoyl group, -   (4-dimethylaminophenyl)carbamoyl group, -   (3-ethoxycarbonylmethoxyphenyl)carbamoyl group, -   (4-ethoxycarbonylmethoxyphenyl)carbamoyl group, -   (3-carboxymethoxyphenyl)carbamoyl group, -   (4-carboxymethoxyphenyl)carbamoyl group, -   (2-methoxycarbonylphenyl)carbamoyl group, -   (3-methoxycarbonylphenyl)carbamoyl group, -   (4-methoxycarbonylphenyl)carbamoyl group, -   (2-benzyloxylcarbonylphenyl)carbamoyl group, -   (pyridin-3-yl)carbamoyl group, -   (pyridin-4-yl)carbamoyl group, -   (2-trifluoromethylpyridin-4-yl)carbamoyl group, -   (2-hydroxymethylpyridin-4-yl)carbamoyl group, -   (2-carboxypyridin-4-yl)carbamoyl group, -   (2-carbamoylpyridin-4-yl)carbamoyl group, -   (2-dimethylcarbamoylpyridin-4-yl)carbamoyl group, -   [2-(cyclopropylcarbamoyl)pyridin-4-yl]carbamoyl group, -   [2-(morpholine-4-carbonyl)pyridin-4-yl]carbamoyl group, -   [2-(pyrrolidine-1-carbonyl)pyridin-4-yl]carbamoyl group, -   (2-chloropyridin-4-yl)carbamoyl group, -   (2-methoxypyridin-4-yl)carbamoyl group, -   (2-tert-butoxycarbonylpyridin-4-yl)carbamoyl group, -   N-methyl-N-(pyridin-4-yl)carbamoyl group, -   [4-(2-hydroxyethyl)thiazol-2-yl]carbamoyl group, -   (pyrimidin-4-yl)carbamoyl group, -   (1-methyl-1H-pyrazol-3-yl)carbamoyl group, -   (1,2,4-triazol-3-yl)carbamoyl group, -   (1,2,4-triazol-4-yl)carbamoyl group, -   (2H-tetrazol-5-yl)carbamoyl group, -   (thiazol-2-yl)carbamoyl group, -   (thiazol-4-yl)carbamoyl group, -   (thiazol-5-yl)carbamoyl group, -   (2-methylthiazol-4-yl)carbamoyl group, -   [4-(1-hydroxy-1-methylethyl)thiazol-2-yl]carbamoyl group, -   (4-ethoxycarbonylmethylthiazol-2-yl)carbamoyl group, -   [4-[2-(morpholin-4-yl)-2-oxoethyl]thiazol-2-yl]carbamoyl group, -   (3-methylisothiazol-5-yl)carbamoyl group, -   (3-methylisoxazol-5-yl)carbamoyl group, -   (5-methylisoxazol-3-yl)carbamoyl group, -   (1,3,4-thiadiazol-2-yl)carbamoyl group, -   (5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl group, -   (5-bromo-1,3,4-thiadiazol-2-yl)carbamoyl group, -   (5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl)carbamoyl group, -   (5-trifluoromethyl-1,3,4-thiadiazol-2-yl)carbamoyl group, -   (5-hydroxymethyl-1,3,4-thiadiazol-2-yl)carbamoyl group, -   [5-(1-hydroxy-1-methylethyl)-1,3,4-thiadiazol-2-yl]carbamoyl group, -   [5-((R)-3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl]carbamoyl     group, -   [5-(4-hydroxypiperidine-1-carbonyl)-1,3,4-thiadiazol-2-yl]carbamoyl     group, -   [5-(morpholine-4-carbonyl)-1,3,4-thiadiazol-2-yl]carbamoyl group, -   (5-acetyl-1,3,4-thiadiazol-2-yl)carbamoyl group, -   (3-methyl-1,2,4-thiadiazol-5-yl)carbamoyl group, -   (1,3,4-oxadiazol-2-yl)carbamoyl group, -   (5-ethoxycarbonyl-1,3,4-oxadiazol-2-yl)carbamoyl group, -   benzylcarbamoyl group, -   phenoxyacetyl group, -   benzylaminoacetyl group, -   2-(pyridin-3-ylamino)acetyl group, -   2-(1-methyl-1H-pyrazol-3-ylamino)acetyl group, -   2-(5-bromo-1,3,4-thiadiazol-2-ylcarbamoyl)acetyl group, -   benzenesulfonylaminocarbonyl group     or the like.

Another preferable embodiment of R is a group other than a hydrogen atom, particularly preferably

wherein each symbol is as defined above.

Here, X is preferably

a bond, —CO—(CH₂)_(p)— or —CONR¹⁰—(CH₂)_(q)—, more preferably a bond.

Ring C is preferably the above-defined “heterocyclic group optionally substituted by 1 to 5 substituents selected from group A”, more preferably the above-defined “heterocyclic group optionally substituted by 1 to 5 substituents selected from group A′”.

The compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably a compound represented by

wherein each symbol is as defined above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, particularly preferably a compound represented by the formula [I-D1], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Ring C2 is preferably, the above-defined “monocyclic heterocyclic group” substituted by 1 to 5 substituents selected from the above-mentioned “group A′”, and the “monocyclic heterocyclic group” moiety is particularly preferably a thiazolyl group (particularly, thiazol-2-yl) or a pyrazinyl group (particularly, pyrazin-2-yl).

Here, the substituent (group A′) on the “monocyclic heterocyclic group” is preferably cyano group, —COOR^(a6), —CONR^(a7)R^(a8), or —SO₂NR^(a9)R^(a10) more preferably —COOR^(a6) or —CONR^(a7)R^(a8).

Another preferable embodiment of ring C2 is the above-defined “fused heterocyclic group” optionally substituted by 1 to 5 substituents selected from the above-mentioned “group A”. The “fused heterocyclic group” moiety is particularly preferably bicyclic fused heterocyclic group, particularly preferably a fused ring of a monocyclic heterocycle and a monocyclic heterocycle.

The “fused heterocyclic group” moiety is specifically preferably pyrido[2,3-b]pyrazin-2-yl group, pyrido[2,3-b]pyrazin-3-yl group, pyrido[3,4-b]pyrazin-2-yl group, pteridin-6-yl group, pteridin-7-yl group, pyrazino[2,3-b]pyrazin-2-yl group, 1H-imidazo[4,5-b]pyrazin-5-yl group, 2,2-dioxo-1,2,3,4-tetrahydropyrazino[2,3-c][1,2,6]thiadiazin-7-yl group, 2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl group, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl group or [1,2,5]thiadiazolo[3,4-b]pyrazinyl group, more preferably pyrido[2,3-b]pyrazin-2-yl group, pyrido[2,3-b]pyrazin-3-yl group, pyrido[3,4-b]pyrazin-2-yl group, pteridin-6-yl group, pteridin-7-yl group, pyrazino[2,3-b]pyrazin-2-yl group, 1H-imidazo[4,5-b]pyrazin-5-yl group or [1,2,5]thiadiazolo[3,4-b]pyrazinyl group, particularly preferably pyrido[3,4-b]pyrazin-2-yl group or pteridin-7-yl group.

Another preferable embodiment of the “fused heterocyclic group” moiety includes

-   benzothiazol-2-yl group, -   4,5,6,7-tetrahydrobenzothiazol-2-yl group, -   thiazolo[5,4-b]pyridin-2-yl group, -   thiazolo[5,4-c]pyridin-2-yl group, -   thiazolo[4,5-d]pyrimidin-2-yl group, -   thiazolo[5,4-d]pyrimidin-2-yl group, -   thiazolo[4,5-d]pyridazin-2-yl group, -   thiazolo[4,5-b]pyrazin-2-yl group, -   thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl group, -   1H-pyrazolo[3,4-d]thiazol-5-yl group, -   4,6-dioxo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl group, -   4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[5,4-c]pyridin-2-yl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-oxo-3,4-dihydrothiazolo[4,5-d][1,2,3]triazin-6-yl group, -   5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl group, and -   [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl group.

More preferably, it includes

-   thiazolo[5,4-b]pyridin-2-yl group, -   thiazolo[5,4-c]pyridin-2-yl group, -   thiazolo[4,5-d]pyrimidin-2-yl group, -   thiazolo[5,4-d]pyrimidin-2-yl group, -   thiazolo[4,5-d]pyridazin-2-yl group, -   thiazolo[4,5-b]pyrazin-2-yl group, -   thiazolo[4,5-d][1,2,3]triazin-6-yl group, -   5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl group, -   4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[5,4-c]pyridin-2-yl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, -   4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, -   4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl group, -   4-oxo-3,4-dihydrothiazolo[4,5-d][1,2,3]triazin-6-yl group, -   5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, -   7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, and -   4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl group.

Still more preferably, it includes thiazolo[4,5-d]pyrimidin-2-yl group, thiazolo[4,5-d]pyridazin-2-yl group, thiazolo[5,4-c]pyridin-2-yl group, 4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group and 7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, more preferably thiazolo[4,5-d]pyrimidin-2-yl group, 4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group and 7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group.

Preferable embodiment of R^(A1) and R^(A2) includes halogen atom, nitro group, cyano group, —OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂R^(a12),

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

A still more preferable embodiment of R^(A1) includes —OR^(a1), —NR^(a3)R^(a4), —NHCOR^(a5), —COOR^(a6), —CONR^(a7)R^(a8), —COR^(a11),

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

A preferable embodiment of R^(A3), R^(A4) and R^(A5) includes halogen atom, nitro group, cyano group,

—OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —COOR^(a6), —CONR^(a7)R^(a8), —COR^(a11), —SO₂R^(a12), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

A still more preferable embodiment of R^(A3) includes —OR^(a1), —NR^(a3)R^(a4), —COOR^(a6), —COR^(a11),

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

A still more preferable embodiment of R^(A4) includes halogen atom, nitro group, cyano group, —OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —COOR^(a6), —CONR^(a7)R^(a8), —COR^(a11), —SO₂R^(a12),

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

A still more preferable embodiment of R^(A5) includes —OR^(a1), —NR^(a3)R^(a4), —NHCOR^(a5), —CONR^(a7)R^(a8), —COR^(a11),

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

A preferable embodiment of R^(A6) and R^(A7) includes hydrogen atom, halogen atom, cyano group, —OR^(a1), —NR^(a3)R^(a4), —COOR^(a6), —CONR^(a7)R^(a8), —COR^(a11), —CONR^(a19)(OR^(a20)),

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

A still more preferable embodiment of R^(A6) includes hydrogen atom, halogen atom, —OR^(a1), —NR^(a3)R^(a4) and —CONR^(a7)R^(a8).

A still more preferable embodiment of R^(A7) includes hydrogen atom, halogen atom, cyano group, —OR^(a1), —NR^(a3)R^(a4), —COOR^(a6), —CONR^(a7)R^(a8), —COR^(a11), —CONR^(a19)(OR^(a20)),

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C, and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

A preferable embodiment of R^(A14) includes —OR^(a1), —NR^(a3)R^(a4) and —CONR^(a7)R^(a8).

A preferable embodiment of R^(A8) and R^(A9) includes hydrogen atom, and

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B.

A preferable embodiment of R^(A10) and R^(A11) includes hydrogen atom, halogen atom, —COOR^(a6), —CONR^(a7)R^(a8), and

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B.

A still more preferable embodiment of R^(A10) includes hydrogen atom, —COOR^(a6), —CONR^(a7)R^(a8), and

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B.

A still more preferable embodiment of R^(A11) includes hydrogen atom and halogen atom.

A preferable embodiment of R^(A12) and R^(A13) includes hydrogen atom, —COOR^(a6), —CONR^(a7)R^(a8), and

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B.

When the carbon atom at the following * moiety of a compound represented by the formula [I] is an asymmetric carbon atom, the compound is preferably an R form:

Examples of the compound represented by the formula [I] include the following compounds.

-   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide hydrochloride (Example 1), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 2), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide (Example 3), -   (R)-4-thiocarbamoyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 4), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid tert-butyl ester (Example 5), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 6), -   (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 7), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 8), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 9), -   (R)-4-acetyl-1-(3-iodo-4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 10), -   4-{5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-trifluoromethoxy-phenyl}-butyric     acid (Example 11), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2-methyl-4-propyl-benzylamide (Example 12), -   2-[(R)-3-[(6-isopropyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 13), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(2-fluoro-4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 14), -   1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide hydrochloride (Example 15), -   1-(4-isopropyl-benzenesulfonyl)-4-methyl-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 16), -   1-(4-isopropyl-benzenesulfonyl)-4-methanesulfonyl-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 17), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 18), -   (S)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 19), -   4-acetyl-1-(4-chloro-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 20), -   4-acetyl-1-(2-chloro-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 21), -   4-acetyl-1-(4-bromo-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 22), -   4-acetyl-1-(5-bromo-thiophene-2-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 23), -   4-acetyl-1-benzenesulfonyl-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 24), -   4-acetyl-1-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 25), -   4-acetyl-1-(4′-chloro-biphenyl-4-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 26), -   4-acetyl-1-[2-(4-cyano-phenoxy)-3,5-dimethyl-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 27), -   4-acetyl-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 28), -   4-acetyl-1-(3-chloro-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 29), -   4-acetyl-1-(4-tert-butyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 30), -   4-acetyl-1-(4-acetyl-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 31), -   4-(4-isopropyl-benzenesulfonyl)-3-(4-trifluoromethyl-benzylcarbamoyl)-piperazine-1-carboxylic     acid methyl ester (Example 32), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-chloro-benzylamide (Example 33), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2-chloro-benzylamide (Example 34), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-chloro-benzylamide (Example 35), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (biphenyl-4-ylmethyl)-amide (Example 36), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 37), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-sulfamoyl-benzylamide (Example 38), -   4-acetyl-1-(4-acetylamino-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 39), -   4-acetyl-1-(4-nitro-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 40), -   4-acetyl-1-(3,4-dichloro-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 41), -   4-acetyl-1-(biphenyl-3-sulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 42), -   4-acetyl-1-[5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 43), -   4-acetyl-1-(4-methoxy-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 44), -   4-acetyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 45), -   4-acetyl-1-(4-cyano-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 46), -   4-acetyl-1-(5-benzenesulfonyl-thiophene-2-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 47), -   4-acetyl-1-(2,3-dihydro-benzofuran-5-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 48), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid benzylamide (Example 49), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2-methoxy-benzylamide (Example 50), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-methoxy-benzylamide (Example 51), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxy-benzylamide (Example 52), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 53), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-bromo-benzylamide (Example 54), -   4-(2-hydroxy-acetyl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 55), -   4-(2-hydroxy-2-methyl-propionyl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 56), -   1-(4-isopropyl-benzenesulfonyl)-4-(2-methoxy-acetyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 57), -   4-(3-hydroxy-propionyl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 58), -   4-(4-isopropyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid     1-dimethylamide 3-(4-trifluoromethyl-benzylamide) (Example 59), -   4-acetyl-1-(4-ethyl-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 60), -   4-acetyl-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 61), -   4-acetyl-1-[5-(4-chloro-pyrazol-1-yl)-thiophene-2-sulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 62), -   4-formyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 63), -   4-acetyl-1-(toluene-4-sulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 64), -   4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 65), -   4-acetyl-1-[4-(pyridin-3-yloxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide hydrochloride (Example 66), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2-fluoro-benzylamide (Example 67), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 68), -   4-acetyl-1-(5-bromo-6-chloro-pyridine-3-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide hydrochloride (Example 69), -   4-acetyl-1-(6-morpholin-4-yl-pyridine-3-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide hydrochloride (Example 70), -   4-acetyl-1-(3-methoxy-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 71), -   4-acetyl-1-(4-propyl-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 72), -   4-acetyl-1-(biphenyl-4-sulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 73), -   4-acetyl-1-(benzo[b]thiophene-2-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 74), -   4-acetyl-1-(5-isopropyl-thiophene-2-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 75), -   4-({[4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carbonyl]-amino}-methyl)-benzoic     acid methyl ester (Example 76), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-nitro-benzylamide (Example 77), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-fluoro-benzylamide (Example 78), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(1H-indol-3-yl)-ethyl]-amide (Example 79), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-morpholin-4-yl-benzylamide (Example 80), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(4-methyl-piperazin-1-yl)-benzylamide (Example 81), -   3-(4-dimethylamino-benzylcarbamoyl)-4-(4-iodo-benzenesulfonyl)-piperazine-1-carboxylic     acid tert-butyl ester (Example 82), -   4-acetyl-1-(4-isopropoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 83), -   1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic acid     4-dimethylamino-benzylamide hydrochloride (Example 84), -   4-acetyl-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic acid     4-dimethylamino-benzylamide (Example 85), -   {2-[3-(4-dimethylamino-benzylcarbamoyl)-4-(4-iodo-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic     acid tert-butyl ester (Example 86), -   {3-[3-(4-dimethylamino-benzylcarbamoyl)-4-(4-iodo-benzenesulfonyl)-piperazin-1-yl]-3-oxo-propyl}-carbamic     acid tert-butyl ester (Example 87), -   4-(2-amino-acetyl)-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide hydrochloride (Example 88), -   4-(3-amino-propionyl)-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide hydrochloride (Example 89), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-amino-benzylamide (Example 90), -   4-acetyl-1-(4-butyl-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 91), -   4-acetyl-1-(4-dimethylamino-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 92), -   4-acetyl-1-(4-amino-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide hydrochloride (Example 93), -   [3-(4-dimethylamino-benzylcarbamoyl)-4-(4-iodo-benzenesulfonyl)-piperazin-1-yl]-acetic     acid methyl ester (Example 94), -   4-(2-dimethylamino-acetyl)-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 95), -   [3-(4-dimethylamino-benzylcarbamoyl)-4-(4-iodo-benzenesulfonyl)-piperazin-1-yl]-acetic     acid (Example 96), -   4-acetyl-1-[4-(1,1-dimethyl-propyl)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 97), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(2,2-dimethyl-propionylamino)-benzylamide (Example 98), -   4-({[4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carbonyl]-amino}-methyl)-benzoic     acid (Example 99), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3,4-dichloro-benzylamide (Example 100), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2,4-dichloro-benzylamide (Example 101), -   1-(4-iodo-benzenesulfonyl)-4-(2-piperidin-1-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 102), -   4-(4,5-dihydro-1H-imidazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 103), -   1-(4-iodo-benzenesulfonyl)-4-(2-morpholin-4-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 104), -   4-(2-benzylamino-acetyl)-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 105), -   4-[4-acetyl-2-(4-trifluoromethyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-benzoic     acid methyl ester (Example 106), -   4-[4-acetyl-2-(4-trifluoromethyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-benzoic     acid (Example 107), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1-methyl-1H-pyrazol-4-yl)-benzylamide (Example 108), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-piperidin-1-yl-benzylamide (Example 109), -   4-(2-dipropylamino-acetyl)-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 110), -   1-(4-isopropyl-benzenesulfonyl)-4-thiocarbamoyl-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 111), -   4-(4,5-dihydro-thiazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 112), -   1-(4-iodo-benzenesulfonyl)-4-(3-morpholin-4-yl-propionyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 113), -   4-(3-dipropylamino-propionyl)-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 114), -   1-(4-isopropyl-benzenesulfonyl)-4-(4-methyl-thiazol-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 115), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (4′-chloro-biphenyl-4-ylmethyl)-amide (Example 116), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 117), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid phenethyl-amide (Example 118), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-trifluoromethyl-benzylamide (Example 119), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2-trifluoromethyl-benzylamide (Example 120), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-trifluoromethoxy-benzylamide (Example 121), -   4-(2-cyclohexyl-acetyl)-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 122), -   4-benzoyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 123), -   1-(4-isopropyl-benzenesulfonyl)-4-phenylacetyl-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 124), -   1-(4-isopropyl-benzenesulfonyl)-4-(2-phenoxy-acetyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 125), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-phenoxy-benzylamide (Example 126), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropoxy-benzylamide (Example 127), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-dimethylamino-benzylamide (Example 128), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2-dimethylamino-benzylamide (Example 129), -   1-(4-iodo-benzenesulfonyl)-4-propionyl-piperazine-2-carboxylic acid     4-dimethylamino-benzylamide (Example 130), -   1-(4-iodo-benzenesulfonyl)-4-phenylacetyl-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 131), -   4-acetyl-1-(4-hydroxymethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 132), -   4-(4,5-dihydro-oxazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 133), -   4-benzothiazol-2-yl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 134), -   1-(4-isopropyl-benzenesulfonyl)-4-(4-phenyl-thiazol-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 135), -   4-acetyl-1-(3,4-dimethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 136), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 137), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(4-chloro-phenyl)-ethyl]-amide (Example 138), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopentyl-benzylamide (Example 139), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1-propyl-butyl)-benzylamide (Example 140), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (3′-chloro-biphenyl-4-ylmethyl)-amide (Example 141), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (2′-chloro-biphenyl-4-ylmethyl)-amide (Example 142), -   4-acetyl-1-(4-methoxymethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 143), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-ethyl-benzylamide (Example 144), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (3-phenyl-propyl)-amide (Example 145), -   (R)-4-carbamoylmethyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 146), -   (R)-4-(2,5-dioxo-pyrrolidin-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 147), -   (R)-4-(2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 148), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(2-chloro-phenyl)-ethyl]-amide (Example 149), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(3-chloro-phenyl)-ethyl]-amide (Example 150), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (6-trifluoromethyl-pyridin-3-ylmethyl)-amide (Example 151), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (pyridin-2-ylmethyl)-amide (Example 152), -   1-(4-iodo-benzenesulfonyl)-4-(2-pyridin-2-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 153), -   1-(4-iodo-benzenesulfonyl)-4-(2-pyridin-3-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 154), -   4-(8H-indeno[1,2-d]thiazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 155), -   1-(4-isopropyl-benzenesulfonyl)-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 156), -   (R)-4-(2-amino-acetyl)-1-(4-iodo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide hydrochloride (Example 157), -   (R)-1-(4-iodo-benzenesulfonyl)-4-(2-piperidin-1-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 158), -   (R)-1-(4-iodo-benzenesulfonyl)-4-(2-pyrrolidin-1-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 159), -   (R)-1-(4-iodo-benzenesulfonyl)-4-(2-morpholin-4-yl-acetyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 160), -   4-acetyl-1-(2,4-dichloro-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 161), -   4-acetyl-1-[4-(1-ethyl-propyl)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 162), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1-ethyl-propyl)-benzylamide (Example 163), -   4-acetyl-1-(naphthalene-2-sulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 164), -   4-acetyl-1-(3-bromo-benzenesulfonyl)-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 165), -   3-{4-[4-acetyl-2-(4-trifluoromethyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenyl}-propionic     acid methyl ester (Example 166), -   4-acetyl-1-(4-cyclohexyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 167), -   3-[4-acetyl-2-(4-trifluoromethyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-benzoic     acid (Example 168), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(2-hydroxy-1,1-dimethyl-ethyl)-benzylamide (Example 169), -   2-[4-(4-isopropyl-benzenesulfonyl)-3-(4-trifluoromethyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid ethyl ester (Example 170), -   2-[4-(4-isopropyl-benzenesulfonyl)-3-(4-trifluoromethyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 171), -   (R)-4-phenylacetyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 172), -   4-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-oxo-butyric     acid methyl ester (Example 173), -   5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-5-oxo-pentanoic     acid methyl ester (Example 174), -   (R)-4-(2-pyridin-3-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 175), -   (R)-4-acetyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 176), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-ethylamide 3-(4-isopropyl-benzylamide) (Example 177), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-phenylamide (Example 178), -   (R)-4-(4,5-dihydro-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 179), -   (R)-4-(2-morpholin-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 180), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-[(2-hydroxy-ethyl)-methyl-amino]-benzylamide (Example 181), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-bromo-2-chloro-benzylamide (Example 182), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2-chloro-4-isopropyl-benzylamide (Example 183), -   (R)-4-(4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 184), -   (R)-4-(2-acetylamino-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 185), -   {3-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-3-oxo-propyl}-carbamic     acid tert-butyl ester (Example 186), -   4-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-oxo-butyric     acid (Example 187), -   (R)-4-(3-acetylamino-propionyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 188), -   (R)-4-(3-amino-propionyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide hydrochloride (Example 189), -   5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-5-oxo-pentanoic     acid (Example 190), -   (R)-4-benzothiazol-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 191), -   (R)-4-acetyl-1-(4-ethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 192), -   (R)-4-acetyl-1-(4-propoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 193), -   (R)-4-acetyl-1-(4-isobutyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 194), -   (R)-4-(2-1H-imidazol-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 195), -   4-acetyl-1-cyclohexanesulfonyl-piperazine-2-carboxylic acid     4-trifluoromethyl-benzylamide (Example 196), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2,4-dimethoxy-benzylamide (Example 197), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3,4-dimethoxy-benzylamide (Example 198), -   4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-butyric     acid (Example 199), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(4-dimethylamino-phenyl)-amide] 3-(4-isopropyl-benzylamide)     (Example 200), -   (R)-4-(pyridine-4-carbonyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 201), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(methyl-propyl-amino)-benzylamide (Example 202), -   (R)-4-acetyl-1-(5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 203), -   (R)-4-acetyl-1-(indane-5-sulfonyl)-piperazine-2-carboxylic acid     4-isopropyl-benzylamide (Example 204), -   (R)-4-acetyl-1-(4-propyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 205), -   (R)-4-acetyl-1-(biphenyl-4-sulfonyl)-piperazine-2-carboxylic acid     4-isopropyl-benzylamide (Example 206), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 207), -   (R)-4-acetyl-1-(4-tert-butyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 208), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide dihydrochloride (Example 209), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methyl-benzylamide (Example 210), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyridin-3-ylamide (Example 211), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-6-oxo-hexanoic     acid methyl ester (Example 212), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-6-oxo-hexanoic     acid (Example 213), -   (R)-4-acetyl-1-(4-methoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 214), -   (R)-4-acetyl-1-(3-isopropyl-4-methoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 215), -   (R)-4-acetyl-1-(3-chloro-4-methoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 216), -   {5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-methoxy-phenyl}-acetic     acid methyl ester (Example 217), -   3-{5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-methoxy-phenyl}-propionic     acid methyl ester (Example 218), -   (R)-4-(2-imidazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 219), -   (R)-4-(2-[1,2,3]triazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 220), -   {5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-methoxy-phenyl}-acetic     acid (Example 221), -   3-{5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-methoxy-phenyl}-propionic     acid (Example 222), -   2-[4-({[(R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic     acid methyl ester (Example 223), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(2-hydroxy-ethyl)-benzylamide (Example 224), -   (R)-4-(2-amino-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide hydrochloride (Example 225), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-hydroxymethyl-benzylamide (Example 226), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methylsulfanyl-benzylamide (Example 227), -   (R)-4-(2-pyrazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 228), -   (R)-4-(2-[1,2,4]triazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 229), -   (R)-4-(2-[1,2,4]triazol-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 230), -   2-[4-({[(R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carbonyl]-amino}-methyl)-phenyl]-2-methyl-propionic     acid (Example 231), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-ethyl-benzylamide (Example 232), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1-dimethylcarbamoyl-1-methyl-ethyl)-benzylamide (Example     233), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1-hydroxymethyl-cyclopropyl)-benzylamide (Example 234), -   5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-methoxy-benzoic     acid methyl ester (Example 235), -   (R)-4-acetyl-1-(3-ethyl-4-methoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 236), -   (R)-4-acetyl-1-[4-(2,2-dimethyl-propyl)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 237), -   {4-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenoxy}-acetic     acid methyl ester (Example 238), -   (R)-4-acetyl-1-(3-cyano-4-methoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 239), -   (R)-4-acetyl-1-(3-tert-butyl-4-methoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 240), -   (R)-4-acetyl-1-(3-cyclopentyl-4-methoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 241), -   (R)-4-(2-[1,2,3]triazol-2-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 242), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-benzylamide 3-(4-isopropyl-benzylamide) (Example 243), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 244), -   (4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-phenoxy)-acetic     acid ethyl ester (Example 245), -   (4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-phenoxy)-acetic     acid (Example 246), -   (R)-4-acetyl-1-(4-propyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-ethyl-benzylamide (Example 247), -   5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-methoxy-benzoic     acid (Example 248), -   {4-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenoxy}-acetic     acid (Example 249), -   3-{4-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenoxy}-propionic     acid methyl ester (Example 250), -   (R)-4-acetyl-1-(4-hydroxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 251), -   N-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-succinamic     acid methyl ester (Example 252), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 253), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid methyl ester (Example 254), -   {2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-acetic     acid methyl ester (Example 255), -   (3-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-phenoxy)-acetic     acid ethyl ester (Example 256), -   (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 257), -   (R)-4-(2-cyano-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 258), -   {2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-acetic     acid (Example 259), -   (3-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-phenoxy)-acetic     acid (Example 260), -   (R)-4-(2-1H-tetrazol-5-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 261), -   (R)-4-(2-amino-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide dihydrochloride (Example 262), -   (R)-4-acetyl-1-(3-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 263), -   (R)-4-acetyl-1-(6,7,8,9-tetrahydro-5H-benzocycloheptene-2-sulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 264), -   (R)-4-benzenesulfonylaminocarbonyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 265), -   (R)-4-[2-(4-methoxy-phenyl)-acetyl]-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 266), -   (R)-4-[2-(2-methoxy-phenyl)-acetyl]-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 267), -   (R)-4-[2-(3-methoxy-phenyl)-acetyl]-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 268), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-chloro-phenyl)-amide] 3-(4-isopropyl-benzylamide)     (Example 269), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(3-chloro-phenyl)-amide] 3-(4-isopropyl-benzylamide)     (Example 270), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(4-chloro-phenyl)-amide] 3-(4-isopropyl-benzylamide)     (Example 271), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-[(2-methoxy-phenyl)-amide]     (Example 272), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-[(3-methoxy-phenyl)-amide]     (Example 273), -   N-[2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl]-succinamic     acid (Example 274), -   3-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-benzoic     acid methyl ester (Example 275), -   4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-benzoic     acid methyl ester (Example 276), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-[(4-methoxy-phenyl)-amide]     (Example 277), -   (R)-4-(2-tetrazol-2-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 278), -   (R)-4-(2-methoxy-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 279), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 280), -   (3-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-phenoxy)-acetic     acid ethyl ester (Example 281), -   (3-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-phenoxy)-acetic     acid (Example 282), -   3-{5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-thiophen-2-yl}-propionic     acid (Example 283), -   (R)-4-acetyl-1-[4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 284), -   4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-benzoic     acid (Example 285), -   3-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-benzoic     acid (Example 286), -   (R)-4-acetyl-1-(5-propyl-thiophene-2-sulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 287), -   (R)-4-acetyl-1-[4-methoxy-3-(2H-tetrazol-5-yl)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 288), -   {5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-thiophen-2-yl}-acetic     acid (Example 289), -   [(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-oxo-acetic     acid ethyl ester (Example 290), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-2-methyl-benzylamide (Example 291), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 2-fluoro-4-isopropyl-benzylamide (Example 292), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-ethyl)-benzylamide (Example 293), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 294), -   (R)-4-(4-propyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid     3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide (Example 295), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid ethyl ester (Example 296), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid methyl ester (Example 297), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 298), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 299), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyrimidin-4-ylamide (Example     300), -   4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic     acid tert-butyl ester (Example 301), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid methyl ester (Example 302), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid methyl ester (Example 303), -   (R)-4-(2-pyridin-4-yl-ethyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 304), -   5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-trifluoromethoxy-benzoic     acid (Example 305), -   (R)-4-acetyl-1-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxine-6-sulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 306), -   (R)-4-acetyl-1-(1-methyl-1,2,3,4-tetrahydro-quinoline-7-sulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 307), -   (R)-4-aminooxalyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 308), -   (2-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic     acid ethyl ester (Example 309), -   (2-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic     acid (Example 310), -   (1-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-tetrazol-5-yl)-acetic     acid ethyl ester (Example 311), -   (1-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-tetrazol-5-yl)-acetic     acid (Example 312), -   (R)-4-carbamimidoyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide hydrochloride (Example 313), -   4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic     acid hydrochloride (Example 314), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 315), -   7-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-7-oxo-heptanoic     acid ethyl ester (Example 316), -   7-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-7-oxo-heptanoic     acid (Example 317), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide (Example 318), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid tert-butyl ester (Example 319), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid tert-butyl ester (Example 320), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-ethyl-2-methyl-benzylamide (Example 321), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 322), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-2-methyl-benzylamide (Example 323), -   3-{5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-trifluoromethoxy-phenyl}-propionic     acid (Example 324), -   4-hydroxy-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic     acid ethyl ester (Example 325), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid tert-butyl ester (Example 326), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid trifluoroacetate (Example 327), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 328), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 329), -   2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid tert-butyl ester (Example 330), -   2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 331), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-[1,3,4]thiadiazol-2-ylamide     (Example 332), -   (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-propyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 333), -   5-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-[1,3,4]oxadiazole-2-carboxylic     acid ethyl ester (Example 334), -   2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 335), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic     acid benzyl ester (Example 336), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic     acid methyl ester (Example 337), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic     acid (Example 338), -   4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 339), -   (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 340), -   4-methyl-2-[(R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 341), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic     acid (Example 342), -   2-[(R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 343), -   2-[(R)-4-(4-isopropyl-benzenesulfonyl)-3-(4-isopropyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 344), -   (R)-4-(2-oxo-pyrrolidin-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 345), -   1-(4-iodo-benzenesulfonyl)-4-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 346), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide (Example 347), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-isopropyl-benzylamide) 1-[1,3,4]oxadiazol-2-ylamide     (Example 348), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-isonicotinic     acid trifluoroacetate (Example 349), -   4-(4-isopropyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid     1-amide 3-(4-trifluoromethyl-benzylamide) (Example 350), -   4-acetyl-1-(3,5-dichloro-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 351), -   (R)-4-(1-methyl-1H-imidazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 352), -   (R)-4-(1H-imidazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 353), -   (R)-4-(4-methyl-5-methylcarbamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 354), -   (R)-4-(5-dimethylcarbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 355), -   2-[(R)-3-(4-cyclopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 356), -   4-hydroxy-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic     acid (Example 357), -   ({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-acetic     acid tert-butyl ester (Example 358), -   3-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic     acid tert-butyl ester (Example 359), -   ({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-acetic     acid (Example 360), -   3-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic     acid (Example 361), -   (R)-4-(5-nitro-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 362), -   4-ethyl-2-[(R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 363), -   2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 364), -   4-methyl-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 365), -   2-[(R)-3-(4-ethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 366), -   2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 367), -   (R)-4-(5-amino-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 368), -   (R)-2-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic     acid (Example 369), -   (S)-2-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic     acid (Example 370), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-oxazole-5-carboxylic     acid trifluoroacetate (Example 371), -   (R)-4-(5-bromo-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 372), -   (R)-4-(2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 373), -   (R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 374), -   (R)-4-acetyl-1-(2-propyl-thiazole-5-sulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 375), -   6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid (Example 376), -   (R)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic     acid 5′-amide 3-(4-isopropyl-benzylamide) (Example 377), -   4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 378), -   2-[(R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid hydrochloride (Example 379), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(5-propyl-thiophene-2-sulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 380), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(6,7,8,9-tetrahydro-5H-benzocycloheptene-2-sulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 381), -   3-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-propionic     acid (Example 382), -   2-[(R)-3-(4-cyclopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 383), -   {2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethylamino}-acetic     acid hydrochloride (Example 384), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 385), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 386), -   2-[(R)-3-[(6-dimethylamino-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 387), -   4-methyl-2-[(R)-3-[(6-propyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 388), -   2-[(R)-3-[(6-azetidin-1-yl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 389), -   4-methyl-2-[(R)-3-[(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 390), -   3-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethylamino}-propionic     acid hydrochloride (Example 391), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(4-methoxy-phenyl)-ethyl]-amide (Example 392), -   4-(2-{[(R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carbonyl]-amino}-ethyl)-benzoic     acid (Example 393), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methoxymethyl-thiazole-5-carboxylic     acid (Example 394), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-pyridin-4-yl-ethyl)-amide (Example 395), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-pyridin-2-yl-ethyl)-amide (Example 396), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-pyridin-3-yl-ethyl)-amide (Example 397), -   2-[(R)-3-(4-azetidin-1-yl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 398), -   (R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 399), -   (R)-4-acetyl-1-(4-cyclopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 400), -   2-[(R)-3-benzylcarbamoyl-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 401), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-piperidin-1-yl-ethyl)-amide (Example 402), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-morpholin-4-yl-ethyl)-amide (Example 403), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (3-morpholin-4-yl-propyl)-amide (Example 404), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid (3-pyrrolidin-1-yl-propyl)-amide (Example 405), -   (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 406), -   (R)-3-[(6-dimethylamino-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 407), -   (R)-3-[(6-isopropyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 408), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 409), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-dimethylamino-benzylamide (Example 410), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 411), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 412), -   4-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-benzoic     acid (Example 413), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 414), -   (R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 415), -   4-methyl-2-[(R)-3-(4-pyrrolidin-1-yl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 416), -   6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid (Example 417), -   4-methyl-2-[(R)-3-phenethylcarbamoyl-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 418), -   (R)-4-acetyl-1-(4-bromo-2-fluoro-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 419), -   (R)-6′-amino-3′-chloro-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 420), -   (R)-6′-bromo-3′-chloro-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 421), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-3′,6′-dimethyl-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 422), -   (R)-6′-amino-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 423), -   2-[(R)-3-[4-(ethyl-methyl-amino)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 424), -   2-[(R)-3-(4-diethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 425), -   5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2H-pyrazole-3-carboxylic     acid (Example 426), -   4-chloro-5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2H-pyrazole-3-carboxylic     acid (Example 427), -   (R)-4-acetyl-1-(4-cyclopropylmethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 428), -   (R)-4-acetyl-1-(2-fluoro-4-propyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 429), -   (R)-4-acetyl-1-(4-bromo-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 430), -   (R)-3-(4-isopropyl-benzylcarbamoyl)-3′-methyl-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 431), -   (R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 432), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(1H-imidazol-4-yl)-ethyl]-amide hydrochloride (Example 433), -   2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-5-methyl-thiazole-4-carboxylic     acid (Example 434), -   (R)-3-(4-propyl-benzylcarbamoyl)-4-(6,7,8,9-tetrahydro-5H-benzenecycloheptene-2-sulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 435), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-propyl-benzylamide) 1-pyridin-4-ylamide (Example 436), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-(4-propyl-benzylamide) 1-[1,3,4]thiadiazol-2-ylamide (Example     437), -   (R)-3-(4-propyl-benzylcarbamoyl)-4-(5-propyl-thiophene-2-sulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 438), -   5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-1-methyl-1H-pyrazole-3-carboxylic     acid (Example 439), -   (R)-4-(4-propyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 440), -   (R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 441), -   2-[(R)-3-(4-ethoxy-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 442), -   (R)-6′-amino-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 443), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-trifluoromethyl-thiazole-5-carboxylic     acid ethyl ester (Example 444), -   5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-methyl-2H-pyrazole-3-carboxylic     acid (Example 445), -   (R)-4-(5-methanesulfonylaminocarbonyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 446), -   (R)-4-(5-methanesulfonylaminocarbonyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 447), -   2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 448), -   (R)-6′-methyl-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 449), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 450), -   2-[(R)-3-(4-methoxymethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 451), -   (R)-4-(5-hydroxymethyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 452), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-trifluoromethyl-thiazole-5-carboxylic     acid (Example 453), -   (R)-4-(6-hydroxy-5-methyl-pyridazin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 454), -   (2-{2-oxo-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-2H-tetrazol-5-yl)-acetic     acid ethyl ester (Example 455), -   (R)-4-[2-(5-methyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 456), -   (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 457), -   (R)-4-(5-amino-pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 458), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 459), -   (R)-4-(2-tetrazol-2-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 460), -   (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 461), -   (R)-4-(2-imidazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 462), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-(methyl-pyridin-4-yl-amide) 3-(4-propyl-benzylamide) (Example     463), -   (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 464), -   (2-{2-oxo-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-2H-tetrazol-5-yl)-acetic     acid (Example 465), -   (2-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic     acid ethyl ester (Example 466), -   (R)-4-[2-(5-methyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 467), -   (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 468), -   (R)-4-acetyl-1-(4-bromo-3-fluoro-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 469), -   (2-{[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-thiazol-4-yl)-acetic     acid ethyl ester (Example 470), -   (R)-5′-amino-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-isopropyl-benzylamide (Example 471), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 472), -   (R)-3-(4-methoxymethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 473), -   (R)-3-(2-chloro-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 474), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-{[4-(2-morpholin-4-yl-2-oxo-ethyl)-thiazol-2-yl]-amide}     3-(4-propyl-benzylamide) (Example 475), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-{[4-(2-hydroxy-ethyl)-thiazol-2-yl]-amide}     3-(4-propyl-benzylamide) (Example 476), -   5-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-[1,3,4]thiadiazole-2-carboxylic     acid ethyl ester (Example 477), -   (R)-4-(4-ethyl-benzenesulfonyl)-5′-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 478), -   (R)-4-[2-(5-phenyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 479), -   (R)-4-[2-(3-methyl-isoxazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 480), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-furan-3-yl-benzylamide (Example 481), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(5-hydroxymethyl-[1,3,4]thiadiazol-2-yl)-amide] (Example 482), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(5-acetyl-[1,3,4]thiadiazol-2-yl)-amide]     3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 483), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[5-(1-hydroxy-1-methyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide}     (Example 484), -   (R)-3-(2-chloro-4-propyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 485), -   4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid methyl ester (Example 486), -   4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid (Example 487), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(5-methyl-[1,3,4]thiadiazol-2-yl)-amide] (Example 488), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amide] (Example 489), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-methoxy-pyridin-4-yl)-amide] (Example 490), -   4-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic     acid tert-butyl ester (Example 491), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-[1,2,3]thiadiazol-4-yl-benzylamide (Example 492), -   {4-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrazol-1-yl}-acetic     acid (Example 493), -   4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid amide (Example 494), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}     (Example 495), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[5-(4-hydroxy-piperidine-1-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}     (Example 496), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[5-(morpholine-4-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}     (Example 497), -   (R)-4-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 498), -   4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(3-propyl-4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 499), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 500), -   (R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 501), -   4-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic     acid (Example 502), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-carbamoyl-pyridin-4-yl)-amide]     3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 503), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-dimethylcarbamoyl-pyridin-4-yl)-amide] (Example 504), -   (R)-4-(5-dimethylaminomethyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 505), -   (R)-4-(4-methyl-5-methylaminomethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 506), -   (R)-6′-amino-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 507), -   (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 508), -   2-[(R)-4-(3-fluoro-4-trifluoromethoxy-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic     acid (Example 509), -   (R)-4-(4-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 510), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-hydroxymethyl-pyridin-4-yl)-amide] (Example 511), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-cyclopropylcarbamoyl-pyridin-4-yl)-amide]     3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 512), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[2-(morpholine-4-carbonyl)-pyridin-4-yl]-amide} (Example 513), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[2-(pyrrolidine-1-carbonyl)-pyridin-4-yl]-amide} (Example 514), -   (R)-6′-acetylamino-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid methyl ester (Example 515), -   (R)-4-(5-oxo-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 516), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-chloro-pyridin-4-yl)-amide]     3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 517), -   (R)-4-[2-(2-methyl-2H-tetrazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 518), -   (R)-4-[2-(1-methyl-1H-tetrazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 519), -   (R)-4-(thiazole-4-carbonyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 520), -   (R)-4-(5-methyl-isoxazole-3-carbonyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 521), -   (R)-4-(5-ethyl-thiophene-2-sulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 522), -   (R)-4-(5-methyl-1H-pyrazol-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-isopropyl-benzylamide (Example 523), -   (R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 524), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-4-ylamide     (Example 525), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(5-methyl-isoxazol-3-yl)-amide] (Example 526), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(3-methyl-[1,2,4]thiadiazol-5-yl)-amide] (Example 527), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(3-methyl-isoxazol-5-yl)-amide] (Example 528), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 529), -   (R)-5′-amino-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 530), -   (R)-4-(4-methyl-5-pyrrolidin-1-ylmethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 531), -   (5-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-tetrazol-2-yl)-acetic     acid ethyl ester (Example 532), -   (5-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-tetrazol-1-yl)-acetic     acid ethyl ester (Example 533), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic     acid benzyl ester (Example 534), -   5-hydroxymethyl-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 535), -   5-methoxymethyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 536), -   5-hydroxymethyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic     acid (Example 537), -   (R)-5′-dimethylaminomethyl-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 538), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[1,2,4]triazol-4-ylamide (Example 539), -   (R)-4-(3-amino-[1,2,4]triazole-1-carbonyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 540), -   (R)-4-[2-(5-isopropyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 541), -   (R)-4-[2-(5-isopropyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 542), -   (R)-4-{2-[5-(2-morpholin-4-yl-2-oxo-ethyl)-tetrazol-2-yl]-acetyl}-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 543), -   (R)-5′-methanesulfonylamino-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 544), -   (R)-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 545), -   (R)-4-(6-hydroxy-pyridazin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 546), -   6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic     acid amide (Example 547), -   (R)-4-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 548), -   (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-propyl-benzylamide (Example 549), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-pentafluoroethyl-benzylamide (Example 550), -   (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-pentafluoroethyl-benzylamide (Example 551), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(5-methyl-[1,3,4]thiadiazol-2-yl)-amide]     3-(4-pentafluoroethyl-benzylamide) (Example 552), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(3-methyl-isothiazol-5-yl)-amide] (Example 553), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-2-ylamide     (Example 554), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-trifluoromethyl-pyridin-4-yl)-amide] (Example 555), -   (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 556), -   (R)-4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 557), -   (R)-5′-pyrrolidin-1-ylmethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 558), -   (R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 559), -   (R)-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 560), -   (R)-4-(5-benzyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 561), -   (R)-4-(4,5-bis-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 562), -   (R)-4-(3-methyl-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 563), -   (R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 564), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(1H-[1,2,4]triazol-3-yl)-amide] (Example 565), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2H-tetrazol-5-yl)-amide] (Example 566), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(2-methyl-thiazol-4-yl)-amide] (Example 567), -   (R)-4-(5-amino-3-methyl-[1,2,4]triazole-1-carbonyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 568), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-[(1-methyl-1H-pyrazol-3-yl)-amide] (Example 569), -   (R)-4-(5-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 570), -   (R)-4-(6-chloro-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 571), -   (R)-4-pyrimidin-4-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 572), -   (R)-4-(4,6-dioxo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 573), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 574), -   (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 575), -   (R)-4-(3-methyl-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 576), -   (R)-4-(5-cyano-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 577), -   (R)-4-(4-oxo-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 578), -   (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 579), -   (R)-4-pyrimidin-4-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 580), -   (R)-4-(2-hydroxy-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 581), -   4-amino-2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid ethyl ester (Example 582), -   (R)-4-[4-methyl-5-(1H-tetrazol-5-yl)-thiazol-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 583), -   (R)-4-(2-amino-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 584), -   (R)-4-(4-amino-pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 585), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic     acid 5′-amide 3-[4-(1,1-difluoro-propyl)-benzylamide] (Example 586), -   2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic     acid tert-butyl ester (Example 587), -   (R)-4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 588), -   (R)-4-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 589), -   (R)-4-(2-pyrimidin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 590), -   (R)-5′-cyano-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 591), -   (R)-5′-(1H-tetrazol-5-yl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 592), -   (R)-5′-morpholin-4-ylmethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 593), -   (R)-5′-(4-methyl-piperazin-1-ylmethyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-tert-butyl-benzylamide (Example 594), -   (R)-5′-dimethylaminomethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 595), -   (R)-4-(3-acetylamino-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 596), -   (R)-4-(4-oxo-4,5-dihydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 597), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide (Example 598), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-thiophen-2-yl-thiazol-4-ylmethyl)-amide (Example 599), -   (R)-4-(5-methanesulfonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 600), -   2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic     acid ethylamide (Example 601), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 602), -   2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-hydroxymethyl-thiazole-5-carboxylic     acid (Example 603), -   (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 604), -   (R)-4-(6-amino-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 605), -   (R)-4-(3-methoxy-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 606), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-5-ylamide     (Example 607), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxy-benzylamide (Example 608), -   (R)-4-isobutyryl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 609), -   (R)-4-cyclopropanecarbonyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 610), -   (R)-4-(2,2-dimethyl-propionyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 611), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 3-[4-(1,1-difluoro-propyl)-benzylamide]     1-{[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-amide} (Example 612), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-hydroxy-benzylamide (Example 613), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-phenyl-thiophen-2-ylmethyl)-amide (Example 614), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 615), -   (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 616), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 617), -   (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 618), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(ethyl-methyl-amino)-benzylamide (Example 619), -   5-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridine-2-carboxylic     acid (Example 620), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (1-hydroxy-cyclohexylmethyl)-amide (Example 621), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid ([2,2′]bithiophenyl-5-ylmethyl)-amide (Example 622), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-thiophen-2-yl-benzylamide (Example 623), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-hydroxy-4-propyl-benzylamide (Example 624), -   (R)-4-(3-methoxy-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 625), -   (R)-4-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 626), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 627), -   (R)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 628), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-chloro-benzylamide (Example 629), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (6-dimethylamino-pyridin-3-ylmethyl)-amide (Example 630), -   5-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridine-2-carboxylic     acid (Example 631), -   (R)-4-quinoxalin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 632), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 633), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-oxo-1-propyl-1,2-dihydro-pyridin-4-ylmethyl)-amide (Example     634), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-amino-4-propyl-benzylamide (Example 635), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-methoxy-benzylamide (Example 636), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-hydroxy-benzylamide (Example 637), -   (R)-6′-amino-5′-aminomethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 638), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (benzoxazol-2-ylmethyl)-amide (Example 639), -   (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 640), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(cyano-dimethyl-methyl)-benzylamide (Example 641), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (biphenyl-2-ylmethyl)-amide (Example 642), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid cyclohexylmethyl-amide (Example 643), -   4-({[(R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carbonyl]-amino}-methyl)-piperidine-1-carboxylic     acid tert-butyl ester (Example 644), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-hydroxy-4-methoxy-benzylamide (Example 645), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-oxo-6-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (Example     646), -   (R)-4-(6-hydroxy-[1,2,5]thiadiazolo[3,4-b]pyrazin-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 647), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 648), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (6-methoxy-5-methyl-pyridin-2-ylmethyl)-amide (Example 649), -   (R)-4-(2,2-dioxo-1,2,3,4-tetrahydro-2λ⁶-pyrazino[2,3-c][1,2,6]thiadiazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 650), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-ethoxy-benzylamide (Example 651), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-thiophen-2-yl-benzylamide (Example 652), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-bromo-benzylamide (Example 653), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (piperidin-4-ylmethyl)-amide hydrochloride (Example 654), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-bromo-benzylamide (Example 655), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 656), -   (R)-4-pteridin-7-yl-1     (4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid     4-methoxymethyl-benzylamide (Example 657), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxy-benzylamide (Example 658), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid ([2,2′]bithiophenyl-5-ylmethyl)-amide (Example 659), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 660), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methylsulfanyl-benzylamide (Example 661), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (1-propyl-1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide (Example     662), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (biphenyl-4-ylmethyl)-amide (Example 663), -   (R)-4-(4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 664), -   (Z)-4-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-oxo-but-2-enoic     acid (Example 665), -   (Z)-4-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-oxo-but-2-enoic     acid (Example 666), -   (E)-4-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-oxo-but-2-enoic     acid (Example 667), -   (E)-4-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-oxo-but-2-enoic     acid (Example 668), -   trans-4-({[(R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carbonyl]-amino}-methyl)-cyclohexanecarboxylic     acid (Example 669), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (1-acetyl-piperidin-4-ylmethyl)-amide (Example 670), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(2-methoxy-phenyl)-ethyl]-amide (Example 671), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(3-methoxy-phenyl)-ethyl]-amide (Example 672), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(4-methoxy-phenyl)-ethyl]-amide (Example 673), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(3-hydroxy-phenyl)-ethyl]-amide (Example 674), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(4-hydroxy-phenyl)-ethyl]-amide (Example 675), -   (R)-4-(1H-imidazo[4,5-b]pyrazin-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 676), -   {[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-acetic     acid (Example 677), -   3-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-3-oxo-propionic     acid (Example 678), -   [(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-oxo-acetic     acid (Example 679), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-oxo-1-propyl-1,2-dihydro-pyridin-4-ylmethyl)-amide (Example     680), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (1-propyl-piperidin-4-ylmethyl)-amide (Example 681), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid [2-(2-hydroxy-phenyl)-ethyl]-amide (Example 682), -   (R)-1-(4-bromo-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 683), -   (R)-4-(6-bromo-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 684), -   (R)-4-(7-bromo-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 685), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 686), -   (R)-4-(4-bromo-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 687), -   (R)-4-(6-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 688), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-tert-butyl-benzylamide (Example 689), -   (R)-4-pyrazino[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 690), -   (R)-4-[1,2,5]thiadiazolo[3,4-b]pyrazin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 691), -   (R)-4-(2-methyl-pteridin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 692), -   2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic     acid ethyl ester (Example 693), -   (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 694), -   (R)-1-(4-tert-butyl-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 695), -   (R)-1-(biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 696), -   (R)-1-(4-chloro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 697), -   (R)-1-(4-nitro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 698), -   (R)-4-(5-bromo-thiophene-2-sulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 699), -   (R)-4-(4-tert-butyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 700), -   (R)-4-(biphenyl-4-sulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 701), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(3-hydroxy-propyl)-benzylamide (Example 702), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (1-propyl-1H-pyrazol-4-ylmethyl)-amide (Example 703), -   (R)-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 704), -   1-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-azetidine-3-carboxylic     acid (Example 705), -   1-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-piperidine-4-carboxylic     acid (Example 706), -   (R)-4-pteridin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 707), -   (R)-1-(4-iodo-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 708), -   (R)-4-pteridin-7-yl-1-(4-thiophen-2-yl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 709), -   3-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic     acid ethyl ester (Example 710), -   3-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic     acid (Example 711), -   2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic     acid (Example 712), -   (R)-1-(4-chloro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 713), -   (R)-1-(4-tert-butyl-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 714), -   (R)-4-thiazolo[5,4-c]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 715), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid [3-(3-hydroxy-phenyl)-propyl]-amide (Example 716), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid [3-(4-hydroxy-phenyl)-propyl]-amide (Example 717), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (6-propyl-pyridin-3-ylmethyl)-amide (Example 718), -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-methyl-pyrazin-2-ylmethyl)-amide (Example 719), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (6-propyl-pyridin-3-ylmethyl)-amide (Example 720), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-methyl-pyrazin-2-ylmethyl)-amide (Example 721), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-amino-4-propyl-benzylamide (Example 722), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-hydroxy-4-propyl-benzylamide (Example 723), -   (R)-1-(2′-hydroxy-biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 724), -   (R)-1-(3′-hydroxy-biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 725), -   (R)-1-(4-nitro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 726), -   (R)-1-(biphenyl-4-sulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 727), -   5-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiophene-2-carboxylic     acid tert-butyl ester (Example 728), -   (2-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetic     acid (Example 729), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide (Example 730), -   (4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-2-yloxy)-acetic     acid (Example 731), -   (4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-3-yloxy)-acetic     acid (Example 732), -   (R)-4-[2-(pyridin-3-ylamino)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 733), -   (R)-4-[2-(1-methyl-1H-pyrazol-3-ylamino)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 734), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 735), -   (R)-1-(4-dimethylamino-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 736), -   (R)-1-(5-bromo-thiophene-2-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 737), -   (R)-1-(benzo[b]thiophene-2-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 738), -   (R)-4-thiazolo[5,4-b]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 739), -   (R)-4-[1,6]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 740), -   (R)-4-(5-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 741), -   (R)-4-(8-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 742), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-pyrrolidin-1-yl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 743), -   trans-[4-(4-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl]-phenyl)-cyclohexyl}-acetic     acid (Example 744), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 745), -   (R)-1-(4-morpholin-4-yl-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 746), -   (R)-1-(4-methoxy-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 747), -   (R)-4-pyrido[2,3-b]pyrazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 748), -   (R)-4-pyrazino[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 749), -   (R)-4-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 750), -   (R)-1-[4-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 751), -   (R)-1-(4-chloro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 752), -   4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-3-carboxylic     acid (Example 753), -   (R)-1-(4-nitro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 754), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-pyrrolidin-1-yl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 755), -   (R)-4-(3H-imidazo[4,5-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 756), -   (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 757), -   (R)-4-(1H-benzimidazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 758), -   (R)-1-[4-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 759), -   (R)-4-pyrido[2,3-b]pyrazin-3-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 760), -   (R)-4-pyrido[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 761), -   (R)-4-pyrido[2,3-b]pyrazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 762), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(2,2,2-trifluoro-ethoxy)-benzylamide (Example 763), -   (methyl-{4-[(R)-4-pyrido[3,4-b]pyrazin-2-yl-2-(4-trifluoromethoxy-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenyl}-amino)-acetic     acid ethyl ester (Example 764), -   (methyl-{4-[(R)-4-pyrido[3,4-b]pyrazin-2-yl-2-(4-trifluoromethoxy-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenyl}-amino)-acetic     acid (Example 765), -   (R)-4-(5-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 766), -   (R)-4-(2-methyl-pteridin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 767), -   (R)-4-thiazolo[5,4-c]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 768), -   (R)-4-pyrido[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 769), -   (R)-4-pyrido[2,3-b]pyrazin-3-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 770), -   (R)-4-[1,6]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 771), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethylsulfanyl-benzylamide (Example 772), -   4-{5-[(R)-2-(4-propyl-benzylcarbamoyl)-4-pteridin-7-yl-piperazine-1-sulfonyl]-2-trifluoromethoxy-phenyl}-butyric     acid (Example 773), -   6-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-nicotinic     acid (Example 774), -   (R)-1-(5-bromo-thiophene-2-sulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 775), -   (R)-4-thiazolo[5,4-b]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 776), -   (R)-1-(4-iodo-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 777), -   (R)-1-(3′-hydroxy-biphenyl-4-sulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 778), -   {4′-[(R)-2-(4-propyl-benzylcarbamoyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-1-sulfonyl]-biphenyl-3-yloxy}-acetic     acid (Example 779), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 780), -   3-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 781), -   (R)-4-quinoxalin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 782), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 783), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 784), -   (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 785), -   (R)-4-(4-ethyl-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 786), -   (R)-4-(5-bromo-thiophene-2-sulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 787), -   (R)-4-(4-pyrrolidin-1-yl-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 788), -   (R)-1-(5-bromo-thiophene-2-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 789), -   (R)-1-(4-nitro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 790), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 791), -   (R)-1-(5-chloro-thiophene-2-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 792), -   (R)-4-[1,5]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 793), -   (R)-4-thiazolo[4,5-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 794), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamide (Example     795), -   (R)-4-(4-ethyl-benzenesulfonyl)-5′-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 796), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 2,4,6-trichloro-benzylamide (Example 797), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(2-trifluoromethyl-pteridin-7-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 798), -   (R)-4-(8-bromo-pyrido[3,4-b]pyrazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 799), -   (R)-4-(5,7-dichloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 800), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 801), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 802), -   (R)-4-(4,7-dioxo-4,5,6,7-tetrahydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 803), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (adamantan-1-ylmethyl)-amide (Example 804), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 805), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 806), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid amide (Example 807), -   3-[2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazin-8-yl]-propionic     acid (Example 808), -   (R)-6′-methyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 809), -   (R)-4-[8-(2-carbamoyl-ethyl)-pyrido[3,4-b]pyrazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 810), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (3-phenyl-propyl)-amide (Example 811), -   (R)-1-(4-ethyl-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 812), -   (R)-4-(8-bromo-pyrido[3,4-b]pyrazin-2-yl)-1-(4-ethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 813), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 814), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 815), -   3-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 816), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-5-carboxylic     acid (Example 817), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-benzothiazole-4-carboxylic     acid (Example 818), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 819), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 820), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 821), -   2-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid (Example 822), -   5-fluoro-2-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-nicotinic     acid (Example 823), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 824), -   (R)-1-(4-nitro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 825), -   3-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-propionic     acid (Example 826), -   (R)-4-(4-methyl-5-sulfamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 827), -   (R)-4-(4-methyl-5-methylsulfamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 828), -   (R)-4-(5-dimethylsulfamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 829), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-phenylamide 3-(4-propyl-benzylamide) (Example 830), -   2-{[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-benzoic     acid methyl ester (Example 831), -   (R)-4-(5-acetylsulfamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 832), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-benzyloxy-phenyl)-amide] 3-(4-propyl-benzylamide)     (Example 833), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(2-hydroxy-phenyl)-amide] 3-(4-propyl-benzylamide) (Example     834), -   (R)-1-(4-nitro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 835), -   2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 836), -   2-{[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-benzoic     acid benzyl ester (Example 837), -   2-{[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-benzoic     acid (Example 838), -   (R)-4-(4-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 839), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-dimethyl-propyl)-benzylamide (Example 840), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-butyl-benzylamide (Example 841), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 842), -   2-[(R)-4-(4-nitro-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 843), -   2-[(R)-4-(4-tert-butyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 844), -   2-[(R)-4-(4-chloro-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 845), -   {4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-oxo-acetic     acid ethyl ester (Example 846), -   4-chloro-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 847), -   {4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-oxo-acetic     acid (Example 848), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (2-phenyl-cyclopropylmethyl)-amide (Example 849), -   (R)-1-(5-chloro-thiophene-2-sulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 850), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(2-methoxy-1,1-dimethyl-ethyl)-benzylamide (Example 851), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic     acid 5′-ethylamide 3-(4-trifluoromethoxy-benzylamide) (Example 852), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic     acid 5′-tert-butylamide 3-(4-trifluoromethoxy-benzylamide) (Example     853), -   2-[(R)-3-[4-(1,1-dimethyl-propyl)-benzylcarbamoyl]-4-(4-ethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 854), -   2-[(R)-3-(4-butyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 855), -   hydroxy-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-acetic     acid ethyl ester (Example 856), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (5-propyl-thiophen-2-ylmethyl)-amide (Example 857), -   2-{(R)-4-(5-chloro-thiophene-2-sulfonyl)-3-[4-(1,1-dimethyl-propyl)-benzylcarbamoyl]-piperazin-1-yl}-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 858), -   (R)-4-(4-methyl-5-methylaminooxalyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 859), -   2-[(R)-4-(5-chloro-thiophene-2-sulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 860), -   2-[(R)-4-(5-chloro-thiophene-2-sulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid (Example 861), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid ethyl ester (Example 862), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid (Example 863), -   (R)-1-(4-fluoro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 864), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid methylamide (Example 865), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid dimethylamide (Example 866), -   (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (1-phenyl-azetidin-3-ylmethyl)-amide (Example 867), -   4-chloro-2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 868), -   (R)-4-(7-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 869), -   (R)-4-(4-hydroxymethyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 870), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic     acid isopropylamide (Example 871), -   (R)-4-(8-cyano-pyrido[3,4-b]pyrazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 872), -   (R)-1-(4-chloro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 873), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid (Example 874), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid methylamide (Example 875), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic     acid amide (Example 876), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 877), -   (R)-4-(5-hydroxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 878), -   (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 879), -   7-chloro-2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid ethyl ester (Example 880), -   (R)-1-(4-bromo-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 881), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1-methoxymethyl-cyclopropyl)-benzylamide (Example 882), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(ethyl-methyl-amino)-benzylamide (Example 883), -   (R)-1-(4-methoxy-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 884), -   (R)-4-thiazolo[5,4-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 885), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 886), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 887), -   (R)-4-(5,7-dihydroxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 888), -   4-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-2-fluoro-benzoic     acid (Example 889), -   4-chloro-2-[(R)-3-[4-(1,1-dimethyl-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 890), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid ethyl ester (Example 891), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid (Example 892), -   (R)-4-(4-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 893), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 894), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 895), -   (R)-4-(7-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 896), -   (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 897), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1,2,2-tetrafluoro-ethoxy)-benzylamide (Example 898), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (3-phenyl-cyclobutylmethyl)-amide (Example 899), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 900), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (naphthalen-2-ylmethyl)-amide (Example 901), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 902), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 903), -   (R)-4-(6-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 904), -   (R)-4-(5-methoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 905), -   (R)-4-(7-chloro-4-methyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 906), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 907), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 908), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (4-methyl-2-propyl-thiazol-5-ylmethyl)-amide (Example 909), -   (R)-4-(5-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 910), -   (R)-4-(5-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 911), -   (R)-4-(5-bromo-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 912), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 913), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-propyl-benzylamide (Example 914), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid amide (Example 915), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid methylamide (Example 916), -   (R)-4-(4-methyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 917), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 918), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 919), -   (R)-4-(7-methyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 920), -   (R)-4-(5-methyl-thiazolo[5,4-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 921), -   (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 922), -   (R)-4-(6-oxo-piperidin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 923), -   (R)-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide hydrochloride (Example 924), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 925), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 926), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 927), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 928), -   (R)-4-(5-methoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 929), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic     acid dimethylamide (Example 930), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 931), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 932), -   (R)-4-(3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 933), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 934), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 935), -   (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic     acid 1-[(5-bromo-[1,3,4]thiadiazol-2-yl)-amide]     3-(4-trifluoromethoxy-benzylamide) (Example 936), -   (R)-4-(4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 937), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(difluoro-methoxy-methyl)-benzylamide (Example 938), -   (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxymethyl-benzylamide (Example 939), -   (R)-4-(4-hydroxymethyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 940), -   (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 941), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 942), -   (R)-4-(5-amino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 943), -   (R)-4-(7-methoxy-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 944), -   (R)-4-(5-dimethylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 945), -   (R)-4-[5-(2-hydroxy-ethylamino)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 946), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(5-trifluoromethyl-thiophene-2-sulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 947), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylic     acid methyl ester (Example 948), -   (R)-4-(5-ethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 949), -   (R)-4-(5-ethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 950), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(3-trifluoromethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 951), -   (R)-4-(5-methylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 952), -   (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 953), -   (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 954), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 955), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 956), -   (R)-4-(5-methyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 957), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(ethyl-methyl-amino)-benzylamide (Example 958), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 959), -   (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 960), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 961), -   (R)-4-(7-amino-5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 962), -   (R)-4-(5-chloro-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 963), -   (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 964), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-methoxy-benzylamide (Example 965), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-fluoromethoxy-benzylamide (Example 966), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-fluoromethoxy-benzylamide (Example 967), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 968), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 969), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 970), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 971), -   (R)-4-(5-fluoro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 972), -   (R)-4-(5-isopropylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 973), -   (R)-4-(5-bromo-7-diethylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 974), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 975), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-cyclopropyl-benzylamide (Example 976), -   (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 977), -   (R)-4-(5-acetyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 978), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid amide (Example 979), -   (R)-4-(1,3-dimethyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 980), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 981), -   (R)-4-(7-amino-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 982), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 983), -   (R)-4-(5-isopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 984), -   (R)-4-(4-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 985), -   (R)-4-(3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 986), -   (R)-4-thiazolo[4,5-d][1,2,3]triazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 987), -   (R)-4-[2-(5-bromo-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 988), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid (indolizin-2-ylmethyl)-amide (Example 989), -   7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylic     acid methylamide (Example 990), -   (R)-4-(5-isopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 991), -   (R)-4-(5-cyclopropylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 992), -   (R)-4-(5-chloro-2-diethylamino-thiazolo[4,5-d]pyrimidin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 993), -   (R)-4-[5-(3-hydroxy-3-methyl-but-1-ynyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 994), -   (R)-4-(5-ethynyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 995), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-pentafluorosulfanyl-benzylamide (Example 996), -   (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 997), -   (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 998), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 999), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1000), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1001), -   (R)-4-[4-(2-hydroxy-ethylamino)-thiazolo[4,5-d][1,2,3]triazin-6-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1002), -   (R)-4-(7-oxo-5-trifluoromethyl-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1003), -   (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1004), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1005), -   (R)-4-thiazolo[4,5-d][1,2,3]triazin-6-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1006), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid ethyl ester (Example 1007), -   (R)-4-(5-hydroxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1008), -   (R)-4-(4-methoxy-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1009), -   (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1010), -   (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1011), -   (R)-4-(5-cyclopropylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1012), -   2-[(R)-3-(4-trifluoromethoxy-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid amide (Example 1013), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1014), -   (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1015), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1016), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1017), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1018), -   (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1019), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1020), -   (R)-4-(7-amino-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1021), -   (R)-4-(7-methoxy-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1022), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1023), -   (R)-4-(5-tert-butyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1024), -   (R)-4-(5-tert-butyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1025), -   (R)-4-(6-chloro-5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1026), -   (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1027), -   (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1028), -   5-methyl-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-7-carboxylic     acid amide (Example 1029), -   (R)-4-(5-methyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1030), -   (R)-4-(4-oxo-3-trifluoromethyl-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1031), -   (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1032), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid (Example 1033), -   (R)-4-(4-amino-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1034), -   (R)-4-(4-methoxy-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1035), -   (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1036), -   (R)-4-(5-ethyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1037), -   (R)-4-(5-oxo-7-trifluoromethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1038), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1039), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 1040), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid dimethylamide (Example 1041), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 1042), -   (R)-4-(5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1043), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 1044), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-2-fluoro-benzylamide (Example 1045), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid methylamide (Example 1046), -   (R)-4-[5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1047), -   (R)-4-(5-acetyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1048), -   (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1049), -   (R)-4-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1050), -   (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1051), -   (R)-4-(5-hydroxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1052), -   (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1053), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic     acid methoxy-methyl-amide (Example 1054), -   (R)-4-(7-amino-5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1055), -   (R)-4-(5-pyrrolidin-1-ylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1056), -   (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1057), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1058), -   (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1059), -   (R)-4-[5-(1-hydroxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1060), -   (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1061), -   (R)-4-(5-oxo-4,5-dihydro-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1062), -   (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1063), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid ethyl ester (Example 1064), -   2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid (Example 1065), -   (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1066), -   (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1067), -   (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1068), -   (R)-4-(5-cyclobutyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1069), -   (R)-4-[5-(2-methoxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1070), -   (R)-4-[5-(2-methoxy-ethyl)-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1071), -   (R)-4-(5-cyclobutyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1072), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1073), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1074), -   (R)-4-[5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1075), -   (R)-4-[5-(1-methoxymethyl-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1076), -   (R)-4-[5-(1-hydroxymethyl-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1077), -   (R)-4-[5-(2-hydroxy-ethyl)-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1078), -   (R)-4-[5-(1-methoxy-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1079), -   (R)-4-[5-(1-hydroxy-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1080), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-6-carboxylic     acid tert-butyl ester (Example 1081), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-6-carboxylic     acid (Example 1082), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid ethyl ester (Example 1083), -   2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid (Example 1084), -   (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1085), -   (R)-4-(5-oxo-4,5-dihydro-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1086), -   (R)-4-(5-difluoromethoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1087), -   (R)-4-(5-isopropyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1088), -   (R)-4-(5-isopropyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-benzylamide (Example 1089), -   (R)-4-(7-amino-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1090), -   (R)-4-[7-amino-5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1091), -   hydroxy-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-acetic     acid (Example 1092), -   4-chloro-2-[(R)-3-[4-(ethyl-methyl-amino)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic     acid (Example 1093), -   {5-methyl-3-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrazol-1-yl}acetic     acid (Example 1094), -   [(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylmethyl]-triethyl-ammonium     trifluoro-methanesulfonate (Example 1095), -   (R)-4-[2-(5-amino-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 1096), -   (R)-4-[2-(5-amino-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-(1,1-difluoro-propyl)-benzylamide (Example 1097), -   (R)-4-[5-(2-hydroxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1098), -   (R)-1-(4-cyclopropyl-benzenesulfonyl)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1099), -   (R)-1-(4-cyclopropyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1100), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-fluoro-4-trifluoromethoxy-benzylamide (Example 1101), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid -   3-fluoro-4-trifluoromethoxy-benzylamide (Example 1102) -   (R)-4-acetyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 3-fluoro-4-trifluoromethoxy-benzylamide (Example 1103), -   2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid (Example 1104), -   (R)-4-(5-hydroxymethyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1105), -   {4-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-4H-thiazolo[4,5-d]pyridazin-5-yl}-acetic     acid (Example 1106), -   (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1107), -   (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1108), -   2-[(R)-3-(4-difluoromethoxy-3-fluoro-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic     acid (Example 1109), -   (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(2-fluoro-4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethoxy-benzylamide (Example 1110), -   (R)-3-(4-difluoromethoxy-3-fluoro-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic     acid (Example 1111), -   3-{4-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-4H-thiazolo[4,5-d]pyridazin-5-yl}propionic     acid (Example 1112), -   (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1113), -   (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-difluoromethoxy-3-fluoro-benzylamide (Example 1114), -   4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 1115), -   (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 1116), and -   (S)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic     acid 4-trifluoromethyl-benzylamide (Example 1117).

The “pharmaceutically acceptable salt” of the compound represented by the formula [I] (hereinafter to be also referred to as the compound of the present invention) may be any salt as long as it forms a nontoxic salt with a compound of the present invention. Examples thereof include a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, a salt with an amino acid and the like.

As the salt with an inorganic acid, for example, salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like can be mentioned.

As the salt with an organic acid, for example, salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.

As the salt with an inorganic base, for example, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like can be mentioned.

As the salt with an organic base, for example, salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine and the like can be mentioned.

As the salt with an amino acid, for example, salts with lysine, arginine, aspartic acid, glutamic acid and the like can be mentioned.

Each salt can be obtained by reacting a compound represented by the formula [I] with an inorganic base, an organic base, an inorganic acid, an organic acid or an amino acid according to a method known per se.

The “solvate” is a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, with which a molecule of a solvent is coordinated, and also encompasses hydrates (also referred to as water-containing compound). The solvate is preferably a pharmaceutically acceptable solvate, such as a monohydrate, a ½ hydrate, a dihydrate, a monohydrate of sodium salt, a monomethanolate, a monoethanolate, a monoacetonitrilate, a ⅔ ethanolate of dihydrochloride of the compound represented by the formula [I] and the like.

A solvate of a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof can be obtained according to a method known per se.

In addition, there are various “isomers” of a compound represented by the above-mentioned formula [I]. For example, E form and Z form are present as geometric isomers. When an asymmetric carbon atom is present, an enantiomer and a diastereomer can be present as stereoisomers based thereon. When an axial asymmetry is present, a stereoisomer based thereon is present. In some cases, a tautomer may be present. Accordingly, all of such isomers and mixtures thereof are encompassed in the scope of the present invention.

In addition, a compound represented by the formula [I] may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S etc.).

The compound represented by the formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably a substantially purified compound represented by the formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is more preferably a compound represented by the formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is purified to a purity of not less than 80%.

In the present invention, a prodrug of a compound represented by the formula [I] can also be a useful pharmaceutical agent. By the “prodrug” is meant a derivative of the compound of the present invention, which has a chemically or metabolically decomposable group and which restores to the original compound to show its inherent efficacy after administration to the body by, for example, hydrolysis, solvolysis or decomposition under physiological conditions. It includes a complex and a salt, not involving a covalent bond. The prodrug is utilized, for example, for improving absorption by oral administration or targeting of a target site.

As the site to be modified, highly reactive functional groups in the compound of the present invention, such as hydroxyl group, carboxyl group, amino group, thiol group and the like, are mentioned.

Examples of the hydroxyl-modifying group include acetyl group, propionyl group, isobutyryl group, pivaloyl group, palmitoyl group, benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl group, dimethylaminomethylcarbonyl group, sulfo group, alanyl group, fumaryl group and the like. In addition, a sodium salt of 3-carboxybenzoyl group, 2-carboxyethylcarbonyl group and the like can be mentioned.

Examples of the carboxyl-modifying group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pivaloyloxymethyl group, carboxymethyl group, dimethylaminomethyl group, 1-(acetyloxy)ethyl group, 1-(ethoxycarbonyloxy)ethyl group, (isopropyloxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, benzyl group, phenyl group, o-tolyl group, morpholinoethyl group, N,N-diethylcarbamoylmethyl group, phthalidyl group and the like.

Examples of the amino-modifying group include tert-butyl group, docosanoyl group, pivaloylmethyloxy group, alanyl group, hexylcarbamoyl group, pentylcarbamoyl group, 3-methylthio-1-(acetylamino)propylcarbonyl group, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, tetrahydrofuranyl group, pyrrolidylmethyl group and the like.

As a pharmaceutical composition containing the compound of the present invention or a salt thereof, or a solvate thereof, oral preparations such as tablet, capsule, granule, powder, troche, syrup, emulsion, suspension and the like, parenteral agents such as external preparation, suppository, injection, eye drop, transnasal agent, pulmonary preparation and the like can be mentioned.

The pharmaceutical composition is produced by appropriately admixing a suitable amount of the compound of the present invention or a salt thereof, or a solvate thereof with at least one kind of a pharmaceutically acceptable carrier according to a method known per se in the technical field of pharmaceutical preparations. The content of the compound of the present invention or a salt thereof in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention or a salt thereof, and the like. It is, for example, 0.1 to 100 wt % of the whole composition.

As the “pharmaceutically acceptable carrier”, various organic or inorganic carrier substances conventionally used as preparation materials can be mentioned. For example, excipient, disintegrant, binder, glidant, lubricant and the like for solid dosage forms, and solvent, solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like for liquid preparations can be mentioned. Where necessary, additives such as preservative, antioxidant, colorant, sweetening agent and the like are used.

As the “excipient”, for example, lactose, sucrose, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, gum arabic and the like can be mentioned.

As the “disintegrant”, for example, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like can be mentioned.

As the “binder”, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like can be mentioned.

As the “glidant”, for example, light anhydrous silicic acid, magnesium stearate and the like can be mentioned.

As the “lubricant”, for example, magnesium stearate, calcium stearate, talc and the like can be mentioned.

As the “solvent”, for example, purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like can be mentioned.

As the “solubilizing agent”, for example, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like can be mentioned.

As the “suspending agent”, for example, benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate and the like can be mentioned.

As the “isotonicity agent”, for example, glucose, D-sorbitol, sodium chloride, D-mannitol and the like can be mentioned.

As the “buffer”, for example, sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like can be mentioned.

As the “soothing agent”, for example, benzyl alcohol and the like can be mentioned.

As the “preservative”, for example, ethyl p-hydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like can be mentioned.

As the “antioxidant”, for example, sodium sulfite, ascorbic acid and the like can be mentioned.

As the “colorant”, for example, foodcolor (e.g., Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5 etc.), β-carotene and the like can be mentioned.

As the “sweetening agent”, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like can be mentioned.

While the dose varies depending on the age, body weight, general condition, treatment effect, administration route and the like, it is from 0.01 mg to 3 g, preferably 0.1 mg to 1 g, for an adult per dose, which is given one to several times a day.

The “prophylaxis of hepatitis C” means, for example, administration of a pharmaceutical agent to an individual found to carry an HCV by a test and the like but without a symptom of hepatitis C, or to an individual who shows an improved disease state of hepatitis after a treatment of hepatitis C, but who still carries an HCV and is associated with a risk of recurrence of hepatitis.

The piperazine compound of the present invention can be used for the improvement of viremia in hepatitis C and/or maintenance of improved condition thereof, treatment of viral infections, particularly, an HCV infection and/or maintenance of improved condition thereof.

HCV is known to be a virus with many gene mutations. Therefore, its effect varies depending on the genotype, so is with interferon. Accordingly, a compound showing an effect for many genotypes is one of the preferable embodiments. HCV type 1a and type 1b are widely distributed all over the world and found in high proportions. Therefore, a compound showing a high effect for the both is particularly preferable.

As an index of the “treatment”, “improvement” or “effect”, a decrease in the virus level or HCV RNA level in the body, particularly in blood, can be used.

The therapeutic agent for hepatitis C of the present invention is expected to provide a synergistic effect when concurrently used with other antiviral agents, antiinflammatory agents or immunostimulants.

The medicaments with the prospect of synergistic effect include, for example, interferon-α, interferon-β, interferon-γ, interleukin-2, interleukin-8, interleukin-10, interleukin-12, TNFα, recombinant or modified products thereof, agonists, antibodies, vaccines, ribozymes, antisense nucleotides and the like.

As evidenced in the combination therapy of anti-HIV agents, which is also called a cocktail therapy, the combined use of various anti-virus agents against viruses showing frequent genetic mutations is expected to show effect for suppressing emergence and increase of drug tolerant viruses. For example, two or three agents from HCV-IRES inhibitors, HCV-NS3 protease inhibitors, HCV-NS2NS3 protease inhibitors, HCV-NS5A inhibitors and HCV polymerase inhibitors may be used in combination. Specifically, the combined use with Ribavirin®, interferon-α IFN-α, Roferon®, Intron A®, Sumiferon®, MultiFeron®, Infergen®, Omniferon®, Pegasys®, PEG-Intron A®), interferon-β (Frone®, Rebif®, AvoneX®, IFNβMOCHIDA®), interferon-γ, interferon-δ, interferon-ω, interferon-τ, consensus interferon, asialointerferon, and Reg interferons thereof, 1-β-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, 16α-bromo-3β-hydroxy-5α-androstan-17-one, 1H-imidazole-4-ethanamide dihydrochloride, HCV ribozyme Heptazyme®, polyclonal antibody Civacir®, lactoferrin GPX-400, (1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizidinium chloride, HCV vaccine (MTH-68/B, Innivax C®, Engerix B®), antisense oligonucleotide ISIS-14803, HCV-RNA transcriptase inhibitor VP-50406, tetrachlorodecaoxide (high concentration Oxoferin®), tetrahydrofuran-3-yl (S)—N-3-[3-(3-methoxy-4-oxazol-5-ylphenyl)ureido]benzylcarbamate, 4-amino-2-ethoxymethyl-α,α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, interleukin-2 (Proleukin®), thymosin α1, VX-497, VX-950, JTK-003, HCV796, R-1626, NM283 and the like is exemplified, wherein (R) shows trade names.

Furthermore, the combined use with the compounds disclosed in JP-A-08-268890, JP-A-10-101591, JP-A-07-069899, WO99/61613 and the like as HCV-IRES inhibitors; the compounds disclosed in WO98/22496, WO99/7733, WO99/7734, WO00/9543, WO00/9558, WO01/59929, WO98/17679, EP932617, WO99/50230, WO00/74768, WO97/43310, U.S. Pat. No. 5,990,276, WO01/58929, WO01/77113, WO02/8198, WO02/8187, WO02/8244, WO02/8256, WO01/7407, WO01/40262, WO01/64678, WO98/46630, JP-A-11-292840, JP-A-10-298151, JP-A-11-127861, JP-A-2001-103993, WO98/46597, WO99/64442, WO00/31129, WO01/32961, WO93/15730, U.S. Pat. No. 7,832,236, WO00/200400, WO02/8251, WO01/16379, WO02/7761 and the like as HCV protease inhibitors; the compounds disclosed in WO97/36554, U.S. Pat. No. 5,830,905, WO97/36866, U.S. Pat. No. 5,633,388, WO01/7027, WO00/24725 and the like as HCV helicase inhibitors; the compounds disclosed in WO00/10573, WO00/13708, WO00/18231, WO00/6529, WO02/6246, WO01/32153, WO01/60315, WO01/77091, WO02/4425, WO02/20497, WO00/4141 and the like as HCV polymerase inhibitors; the compounds disclosed in WO01/58877, JP-A-11-180981, WO01/12214 and the like as interferon agonists or enhancers; and the like is also exemplified.

In the case of combined administration, the compound of the present invention can be administered simultaneously with a pharmaceutical agent to be used in combination (hereinafter combination drug) or administered at certain time intervals. In the case of combined administration, a pharmaceutical composition containing the compound of the present invention and a combination drug can be administered. Alternatively, a pharmaceutical composition containing the compound of the present invention and a pharmaceutical composition containing a combination drug may be administered separately. The administration route of the compound of the present invention and that of the combination drug may be the same or different.

In the case of a combined administration, the compound of the present invention can be administered once a day or several times a day in a single dose of 0.01 mg to 3 g, preferably 0.1 mg to 1 g, or may be administered at a smaller dose. The combination drug can be administered at a dose generally used for the prevention or treatment of hepatitis C, for example, at a single dose of 0.01 mg to 2 mg. Alternatively, it may be administered at a smaller dose.

Examples of the production method of the compound of the present invention to be used for the practice of the present invention are given in the following. However, the production method of the compound of the present invention is not limited to these examples.

Even if no directly corresponding disclosure is found in the following Production Methods, the steps may be modified for efficient production of the compound, such as introduction of a protecting group into a functional group with deprotection in a subsequent step, and changing the order of Production Methods and steps.

The treatment after reaction in each step may be conventional ones, for which typical methods, such as isolation and purification, crystallization, recrystallization, silica gel chromatography, preparative HPLC and the like, can be appropriately selected and combined.

Production Method 1-1

wherein R^(C1) is an amine protecting group, Hal¹ is a halogen atom, R^(C2) and R^(C3) are the same or different and each is a hydroxyl group or a leaving group, wherein compound [7] and compound [8] may be an acid anhydride represented by ring C—Y¹—C(═O)—O—C(═O)—Y¹-ring C or Y²—C(═O)—O—C(═O)—Y², respectively, Y¹ is *—(CH₂)_(p)—, *—NR¹⁰—(CH₂)_(q)—, *—(CH₂)_(r)—O—(CH₂)_(s)—, *—(CH₂)_(t)—NH—(CH₂)_(u)—, —(CH₂)_(v)—CONH—(CH₂)_(w)— or *—NH—SO₂—, Y² is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, *—OR², *—COOR⁶, —CH═CH—COOR¹¹, *—(CH₂)_(a)—NH—R⁷, *—(CH₂)_(b)—NHCOR⁸, *—(CH₂)_(c)—NHCOOR⁹ or *—CONH₂, wherein * shows the side bonded to the carbonyl group, and other symbols are as defined above.

As the leaving group, fluorine atom, chlorine atom, bromine atom, iodine atom, p-nitrophenyloxy group, azido group and the like can be mentioned.

As the amine protecting group, benzoyl group, tert-butyl group, tert-butylcarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, trifluoroacetyl group, fluorenylmethoxycarbonyl group and the like can be mentioned.

Step 1

Compound [2] can be obtained by introducing a protecting group into compound [1] according to a conventional method.

For example, when R^(C1) is tert-butoxycarbonyl group, compound [1] is treated with tert-butoxycarbonyl chloride, 2-tert-butyloxycarbonyl-oxyimino-2-phenylacetonitrile or di-tert-butyl dicarbonate under cooling to room temperature in a solvent such as tetrahydrofuran (THF), 1,4-dioxane, a mixed solvent thereof with water and the like in the presence or absence of a base such as sodium hydroxide and the like.

Step 2

Compound [4] can be obtained by reacting compound [2] with compound [3] in a solvent in the presence of a base in the presence or absence of a catalyst such as 4-(dimethylamino)pyridine and the like.

As the solvent, a single or mixed solvent of water, 1,4-dioxane, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride, toluene, pyridine, N,N-dimethylformamide (DMF) and the like can be mentioned, with preference given to chloroform and a mixed solvent of 1,4-dioxane and water.

As the base, triethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, sodium hydroxide, potassium carbonate and the like can be mentioned, preferably, triethylamine.

As the Hal¹, preferred is a chlorine atom.

Step 3

Compound [6] can be obtained by amide condensation of carboxylic acid compound [4] with amine compound [5] in a solvent in the presence of a condensing agent.

Compound [6] can also be obtained by a method including affording a reactive derivative of carboxylic acid compound [4] by converting carboxylic acid compound [4] to an acid halide induced with thionyl chloride, oxalyl chloride etc. (optionally adding a catalytic amount of DMF), or converting to a mixed acid anhydride induced with ethyl chlorocarbonate etc., and the like, and then reacting the reactive derivative with amine compound [5] in the presence of a base.

As the solvent, DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride, toluene and the like can be mentioned, with preference given to DMF.

As the condensing agent, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diphenylphosphoryl azide and the like can be mentioned. As necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like can be added.

As the base, potassium carbonate, triethylamine, pyridine, 4-(dimethylamino)pyridine, N-methylmorpholine, diisopropylethylamine and the like can be mentioned, with preference given to triethylamine.

Step 4

Compound [I-1] can be obtained by eliminating the amine protecting group of compound [6] by a conventional method.

For example, when R^(C1) tert-butoxycarbonyl group, deprotection can be performed by a method including treatment with a hydrogen chloride-ethyl acetate solution at room temperature in an ethyl acetate or methanol solution; treatment with hydrochloric acid in tetrahydrofuran at room temperature; treatment with a hydrogen chloride-1,4-dioxane solution in a methanol or chloroform solvent at room temperature; treatment with trifluoroacetic acid in a chloroform solution and the like.

Step 5

In this step, R^(C2) is a hydroxyl group or a leaving group, and a preferable leaving group is chlorine atom.

When R^(C2) is a hydroxyl group, compound [I-2] can be obtained in the same manner as in production method 1-1, step 3, by reacting compound [I-1] with compound [7]

When R^(C2) is a leaving group, compound [I-2] can be obtained by reacting compound [I-1] with compound [7] in a solvent in the presence of a base.

As the solvent, DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride, toluene and the like can be mentioned, with preference given to DMF, THF and chloroform.

As the base, potassium carbonate, triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine and the like can be mentioned, with preference given to triethylamine.

Step 6

In this step, R^(C3) is a hydroxyl group or a leaving group, and the leaving group is preferably chlorine atom. Compound [8] which is an acid anhydride represented by Y²—C(═O)—O—C(═O)—Y² is one of the preferable embodiments.

Compound [I-3] can be obtained by reacting compound [I-1] with compound [8] in the same manner as in the previous step.

Production Method 1-2

wherein R^(C4) and R^(C5) are the same or different and each is a leaving group, Y³ is a bond or C₁₋₄ alkylene, Y⁴ is —SO₂R⁵ or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, and other symbols are as defined above.

Step 1

In this step, R^(C4) is a leaving group, preferably, fluorine atom, chlorine atom, bromine atom, iodine atom, methylthio group, methylsulfinyl group, methylsulfonyl group, methanesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like, more preferably, fluorine atom, chlorine atom, bromine atom, iodine atom, methylthio group or methylsulfonyl group.

Compound [I-4] can be obtained by reacting compound [I-1] with compound [9] in a solvent in the presence of a base.

As the solvent, alcohol solvents such as ethanol, isopropanol and the like, DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride, toluene and the like can be mentioned.

As the base, potassium carbonate, triethylamine, pyridine, 4-(dimethylamino)pyridine, diisopropylethylamine and the like can be mentioned.

Step 2

In this step, R^(C5) is a leaving group, with preference given to chlorine atom, bromine atom and iodine atom.

In the same manner as in the previous step, compound [I-5] can be obtained by reacting compound [I-1] with compound [10].

Production Method 1-3

wherein each symbol is as defined above.

Step 1

Compound [I-6] can be obtained by reacting compound [11] with carbonyldiimidazole or triphosgene in a solvent in the presence or absence of a base, and then by reacting with compound [I-1] in the presence of a base.

As the solvent, chloroform, DMF, acetonitrile, THF, ethyl acetate, methylene chloride, toluene and the like can be mentioned, with preference given to chloroform.

As the base, triethylamine, potassium carbonate, pyridine, 4-(dimethylamino)pyridine, diisopropylethylamine and the like can be mentioned, with preference given to triethylamine.

Step 2

In the same manner as in the previous step, compound [I-7] can be obtained by reacting compound [12] with compound [I-1].

Production Method 1-4

wherein R^(C6) is an amine protecting group, R^(C7) is a halogen atom, Y⁵ is an oxygen atom or a sulfur atom, R^(A1) and R^(A2) are the same or different and each is a substituent selected from group A, and other symbols are as defined above.

Using, as compound [14], a compound wherein R^(A1) and R^(A2) in combination form a ring, a fused ring such as 4,5,6,7-tetrahydrobenzothiazole, 4,5,6,7-tetrahydrobenzoxazole, 8H-indeno[1,2-d]thiazole and the like can also be formed.

Step 1

Compound [I-8] can be obtained by reacting compound [I-1] with compound [13] in a solvent in the presence of a base.

As the solvent, chloroform, DMF, acetonitrile, THF, ethyl acetate, methylene chloride, toluene and the like can be mentioned, with preference given to chloroform.

As the base, potassium carbonate, triethylamine, pyridine, 4-(dimethylamino)pyridine, diisopropylethylamine and the like can be mentioned, with preference given to triethylamine.

Step 2

Compound [I-9] can be obtained by deprotecting compound [I-8] by a conventional method.

For example, when R^(C6) is fluorenylmethoxycarbonyl group, compound [I-9] can be obtained by reacting compound [I-8] in the presence of a base.

As the base, piperidine, 4-(dimethylamino)pyridine, morpholine, dicyclohexylamine, diisopropylethylamine, tetrabutylammonium fluoride and the like can be mentioned, with preference given to piperidine.

Step 3

Compound [I-10] can be obtained by reacting compound [I-9] with compound [14] in a solvent under heating.

As the solvent, acetonitrile, methanol, ethanol, isopropanol, DMF, N-methylpyrrolidone, THF, toluene and the like can be mentioned, with preference given to acetonitrile.

Production Method 1-5

wherein R^(C8) and R^(C9) are amine protecting groups, R^(C10) is a C₁₋₄ alkyl group such as methyl group, ethyl group and the like, R^(A3), R^(A4) and R^(A5) are the same or different and each is a substituent selected from group A, and other symbols are as defined above.

Step 1

Compound [I-11] can be obtained by reacting compound [I-1] with compound [16] in a solvent in the presence or absence of a base.

As the solvent, acetonitrile, methanol, ethanol, isopropanol, DMF, THF, toluene and the like can be mentioned, with preference given to acetonitrile and DMF.

As the base, potassium carbonate, triethylamine, pyridine, 4-(dimethylamino)pyridine, diisopropylethylamine and the like can be mentioned, with preference given to diisopropylethylamine.

Step 2

Compound [I-12] can be obtained by eliminating the amine protecting group of compound [I-11] by a conventional method.

R^(C8) and R^(C9) are preferably tert-butoxycarbonyl groups.

Step 3

Compound [I-13] can be obtained by reacting compound [I-12] with compound [14] in a solvent in the presence or absence of a base.

As the solvent, acetonitrile, methanol, ethanol, isopropanol, DMF, THF, toluene, 1,4-dioxane and the like can be mentioned, with preference given to methanol and ethanol.

As the base, sodium ethoxide, sodium methoxide, potassium carbonate, potassium hydrogen carbonate, sodium acetate, ammonia and the like can be mentioned, with preference given to sodium ethoxide and sodium methoxide.

Step 4

In the same manner as in production method 1-5, step 3, compound [I-14] can be obtained by reacting compound [I-12] with compound [17].

Production Method 2

wherein R^(C11) is an amine protecting group, and other symbols are as defined above.

Step 1

Compound [18] can be obtained from compound [1] in the same manner as in production methods 1-1 to 1-5, or by a conventional method.

Step 2

Compound [19] can be obtained by introducing a protecting group into compound [18] according to a conventional method.

R^(C11) is preferably tert-butoxycarbonyl group.

Step 3

Compound [20] can be obtained by reacting compound [19] with compound [5] in the same manner as in production method 1-1, step 3.

Step 4

Compound [21] can be obtained by eliminating the amine protecting group of compound [20] by a conventional method.

Step 5

Compound [I] can be obtained by reacting compound [21] with compound [3] in the same manner as in production method 1-1, step 2.

Production Method 3

wherein each symbol is as defined above.

Step 1

Compound [18] can be obtained from compound [1] in the same manner as in production methods 1-1 to 1-5, or by a conventional method.

Step 2

Compound [22] can be obtained by reacting compound [18] with compound [3] in the same manner as in production method 1-1, step 2.

Step 3

Compound [I] can be obtained by reacting compound [22] with compound [5] in the same manner as in production method 1-1, step 3.

Production Method 4

wherein R^(C13) is a carboxylic acid protecting group, and other symbols are as defined above.

As the carboxylic acid protecting group, methyl group, ethyl group, tert-butyl group, benzyl group, allyl group, tetrahydropyranyl group and the like can be mentioned.

Step 1

Compound [23] can be obtained by introducing a protecting group into the carboxyl group of compound [4] according to a conventional method.

For example, when R^(C13) is benzyl group, compound [23] can be obtained by reacting compound [4] with benzyl alcohol in a chloroform solvent in the presence or absence of a catalyst such as 4-(dimethylamino)pyridine and the like in the presence of a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like.

Step 2

Compound [24] can be obtained by eliminating an amine protecting group of compound [23] by a conventional method.

R^(C1) is preferably tert-butoxycarbonyl group.

Step 3

Compound [25] can be obtained from compound [24] in the same manner as in production methods 1-1 to 1-5, or by a conventional method.

Step 4

After removing R^(C13) by a conventional method, compound [I] can be obtained by reacting compound [25] with compound [5] in the same manner as in production method 1-1, step 3.

Production Method 5

wherein R^(C14) and R^(C15) are the same or different and each is an amine protecting group, and other symbols are as defined above.

Step 1

Compound [27] can be obtained by reacting compound [26] obtained by a conventional method with compound [5] in the same manner as in production method 1-1, step 3.

Step 2

Compound [28] can be obtained by eliminating the amine protecting group of compound [27] by a conventional method.

The combination of R^(C14) and R^(C15) refers to the combination of benzyloxycarbonyl group and tert-butoxycarbonyl group, trifluoroacetyl group and benzyloxycarbonyl group, trifluoroacetyl group and tert-butoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group and benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group and tert-butoxycarbonyl group and the like can be mentioned, with preference given to a combination of benzyloxycarbonyl group and tert-butoxycarbonyl group.

Step 3

Compound [29] can be obtained from compound [28] in the same manner as in production methods 1-1 to 1-5, or by a conventional method.

Step 4

Compound [30] can be obtained by eliminating the amine protecting group of compound [29] by a conventional method.

Step 5

Compound [I] can be obtained by reacting compound [30] with compound [3] in the same manner as in production method 1-1, step 2.

Production Method 1-2-1

When, in R^(C4)—Y³-ring C (compound [9]), Y³ is a bond and ring C is thiazolo[4,5-d]pyrimidin-2-yl optionally substituted by a substituent selected from group A, compound [I] can also be produced by the following method.

This production method is applicable even when the pyrimidine moiety of thiazolo[4,5-d]pyrimidin-2-yl is, for example, other aryl group.

wherein R^(A6) and R^(A7) are the same or different and each is a hydrogen atom or a substituent selected from group A, Hal² is a halogen atom such as a bromine atom, a chlorine atom and the like, and other symbols are as defined above.

Step 1

Compound [31] can be obtained by reacting compound [30] with thiocyanate such as potassium thiocyanate, sodium thiocyanate, ammonium thiocyanate and the like and halogen in a solvent in the presence of a base.

As the solvent, an alcohol solvent such as methanol, ethanol and the like, or DMF, THF, toluene and the like can be mentioned, with preference given to DMF and methanol.

As the base, pyridine, 4-(dimethylamino)pyridine and the like can be mentioned, with preference given to pyridine.

As the halogen, bromine is preferable.

Step 2

Compound [32] can be obtained by heating compound [31] in a solvent.

As the solvent, hydrous or anhydrous DMF, dimethyl sulfoxide (DMSO) and the like can be mentioned, with preference given to anhydrous DMF.

In addition, compound [32] can also be obtained by heating compound [31] with acetic anhydride, and treating the obtained compound with an alkali solution such as aqueous sodium carbonate solution, aqueous sodium hydroxide solution and the like.

Step 3

Compound [33] can be obtained by substituting the amino group of compound [32] by a leaving group by a conventional method.

For example, when Hal² is a chlorine atom, compound [33] can be obtained by adding sodium nitrite to compound [32] suspended in an aqueous sodium hydroxide solution, then adding hydrochloric acid, or adding sodium nitrite to a solution of compound [32] in hydrochloric acid, or adding hydrochloric acid to a solution of compound [32] in acetic acid and then adding sodium nitrite.

Hal² is preferably a chlorine atom.

Step 4

Compound [I-15] can be obtained by reacting compound [33] with compound [I-1] in the same manner as in production method 1-2, step 1.

Production Method 1-2-1-1

Production example for converting substituent on thiazolo[4,5-d]pyrimidin-2-yl group

wherein Hal³ is a halogen atom, R^(A14) is a substituent selected from the following group A1, and other symbols are as defined above: group A1: nitro group, cyano group,

OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13),

a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C, a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C, and, a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C.

Step 1

Compound [31-1] can be obtained from compound [30-1] in the same manner as in production method 1-2-1, step 1.

Step 2

Compound [32-1] can be obtained from compound [31-1] in the same manner as in production method 1-2-1, step 2.

Step 3

Compound [33-1] can be obtained by substituting the amino group of compound [32-1] by a halogen atom by a conventional method in the same manner as in production method 1-2-1, step 3.

Step 4

Compound [33-2] can be obtained by substituting the hydroxyl group of compound [33-1] by a halogen atom by a conventional method.

For example, compound [33-2] can be obtained by reacting compound [33-1] without a solvent or in a solvent in the presence of a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride and the like under heating conditions.

To promote the reaction, water or a base such as N,N-dimethylaniline, triethylamine, N,N-diisopropylethylamine and the like may be added.

As the solvent, dichloromethane, chloroform, 1,4-dioxane, THF and the like can be mentioned.

Step 5

Compound [I-20] can be obtained by reacting compound [33-2] with compound [I-1] in the same manner as in production method 1-2, step 1.

Step 6

Compound [I-21] can be obtained by reducing Hal³ of compound [I-20] by a conventional method.

For example, compound [I-21] can be obtained by reacting compound [I-20] in an alcohol solvent such as methanol, ethanol and the like in the presence of ammonium formate using a catalyst such as palladium carbon, palladium hydroxide and the like under heating conditions.

Step 7

Compound [I-22] can be obtained by introducing and substituting a substituent into Hal³ of compound [I-20] by a conventional method.

Production Method 1-2-2

When, in R^(C4)—Y³-ring C (compound [9]), Y³ is a bond, and ring C is pteridin-7-yl optionally substituted by a substituent selected from group A, compound [I] can also be produced by the following method.

This production method is applicable even when the pyrimidine moiety of pteridin-7-yl is, for example, other aryl group.

wherein R^(A8) and R^(A9) are the same or different and each is a hydrogen atom or a substituent selected from group A, R^(C16) and R^(C17) are the same or different and each is a C₁₋₄ alkyl group such as methyl group, ethyl group and the like, and other symbols are as defined above.

Step 1

Compound [36] can be obtained by reacting compound [34] with compound [35] in a solvent in the presence of a base under heating conditions.

As the combination of solvent and base, a combination of a mixed solvent of acetic acid and water and sodium acetate is preferable.

Step 2

Compound [37] can be obtained by substituting the hydroxyl group of compound [36] by a leaving group by a conventional method.

For example, when R^(C4) is a chlorine atom, compound [37] can be obtained by heating compound [36] in a solvent in the presence of a halogenating agent such as phosphorus oxychloride, phosphorus pentachloride and the like.

As the solvent, pentachloroethane, DMF, xylene, pyridine and the like can be mentioned, with preference given to pentachloroethane.

Step 3

Compound [I-16] can be obtained by reacting compound [37] with compound [I-1] in the same manner as in production method 1-2, step 1.

Production Method 1-2-3-1

When, in R^(C4)—Y³-ring C (compound [9]), Y³ is a bond and ring C is 7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl optionally substituted by a substituent selected from group A, compound [I] can also be produced by the following method.

wherein R^(A10) and R^(A11) are the same or different and each is a substituent selected from the above-mentioned group A1, Hal⁴ is a halogen atom such as bromine atom, chlorine atom and the like, and other symbols are as defined above.

Step 1

Compound [39] can be obtained by introducing a leaving group into compound [38] by a conventional method.

For example, when R^(C4) is a halogen atom, Compound [39] can be obtained by reacting compound [38] with halogen in the presence of acetic acid and sodium acetate.

Step 2

Compound [41] can be obtained by reacting compound [39] with compound [40] in a solvent under heating conditions.

In addition, compound [41] wherein R^(A10) is methyl group can be obtained by using 4-methyleneoxetan-2-one instead of compound [40].

As the solvent, DMF, THF, toluene and the like can be mentioned, with preference given to toluene.

Step 3

Compound [42] can be obtained by reacting compound [41] in the presence of an acid such as concentrated sulfuric acid, concentrated hydrochloric acid, acetic acid, trifluoroacetic acid and the like under heating conditions.

Step 4

Compound [I-17] can be obtained by reacting compound [42] with compound [I-1] in the same manner as in production method 1-2, step 1.

Step 5

Compound [42-1] can be obtained by halogenating compound [42] by a conventional method.

Step 6

Compound [42-2] can be obtained by introducing and substituting a substituent into Hal⁴ of compound [42-1] by a conventional method.

Step 7

Compound [I-17-1] can be obtained by reacting compound [42-2] with compound [I-1] in the same manner as in production method 1-2, step 1.

Production Method 1-2-3-2

When, in R^(C4)—Y³-ring C (compound [9]), Y³ is a bond and ring C is 7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl optionally substituted by a substituent selected from group A, compound [I] can also be produced by the following method.

wherein R^(C22) is a carboxylic acid protecting group, and other symbols are as defined above.

Step 1

Compound [39] can be obtained by introducing a leaving group into compound [38] by a conventional method in the same manner as in production method 1-2-3-1, step 1.

Step 2

Compound [42-1] can be obtained by reacting compound [39] with compound [63] in an alcohol solvent such as methanol, tert-butyl alcohol and the like under heating conditions.

Step 3

Compound [64] can be obtained by reacting compound [42-1] with compound [I-1] in the same manner as in production method 1-2, step 1.

Step 4

Compound [I-17-2] can be obtained by eliminating the carboxylic acid protecting group of compound [64] by a conventional method.

Step 5

Compound [I-17-3] can be obtained by heating compound [I-17-2] in a solvent.

As the solvent, diphenyl ether, diethylene glycol and the like can be mentioned.

Production Method 1-2-4

When, in R^(C4)—Y³-ring C (compound [9]), Y³ is a bond, and ring C is 7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl optionally substituted by a substituent selected from group A, compound [I] can also be produced by the following method.

wherein R^(A12) is a hydrogen atom or a substituent selected from group A, R^(A13) is a substituent selected from group A, R^(C19) is a carboxylic acid protecting group, R^(C20) is a hydroxyl protecting group, Hal⁵ is a halogen atom such as a chlorine atom, a bromine atom and the like, and other symbols are as defined above.

As the hydroxyl protecting group, methyl group, ethyl group, tert-butyldimethylsilyl group, acetyl group, benzyl group, methoxyethoxymethyl group and the like can be mentioned.

Step 1

Compound [44] can be obtained by reacting compound [43] with thiourea in an alcohol solvent such as methanol, ethanol and the like, or in an acetonitrile solvent, under heating conditions.

Step 2

Compound [45] can be obtained by eliminating the hydroxyl protecting group of compound [44] by a conventional method.

For example, when R^(C20) is methyl group, compound [45] can be obtained by adding boron tribromide to compound [44] in a dichloromethane solvent, and then adding aqueous sodium hydroxide solution.

Step 3

Compound [46] can be obtained by oxidizing compound [45] by a conventional method.

For example, compound [46] can be obtained by treating compound [45] with manganese dioxide in a solvent such as chloroform, dichloroethane, 1,4-dioxane, DMF and the like, or a mixed solvent thereof.

Step 4

Compound [48] can be obtained by reacting compound [46] with compound [47] in an alcohol solvent such as methanol, ethanol and the like under heating conditions.

To promote the reaction, acetic acid may be added.

Step 5

In the same manner as in production method 1-2-1, step 3, compound [49] can be obtained by converting the amino group of compound [48] to a leaving group.

Step 6

Compound [I-18] can be obtained by reacting compound [49] with compound [I-1] in the same manner as in production method 1-2, step 1.

Step 7

Compound [I-18-1] can be obtained by introducing a substituent selected from group A into the nitrogen atom on compound [I-18] by a conventional method.

Compound [I-18-1] can also be obtained by performing the production methods of step 5 and step 6 using R^(A13)—NH—NH₂ instead of compound [47].

Production Method 1-2-5

When, in R^(C4)—Y³-ring C (compound [9]), Y³ is a bond and ring C is 4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl optionally substituted by a substituent selected from group A, compound [I] can also be produced by the following method.

wherein each symbol is as defined above.

Step 1

Compound [51] can be obtained by reacting compound [50] with thiourea in the same manner as in production method 1-2-4, step 1.

Step 2

In the same manner as in production method 1-2-4, step 2, compound [52] can be obtained by eliminating the hydroxyl protecting group of compound [51] by a conventional method.

Step 3

In the same manner as in production method 1-2-4, step 3, compound [53] can be obtained by oxidizing compound [52] by a conventional method.

Step 4

In the same manner as in production method 1-2-4, step 4, compound [54] can be obtained by reacting compound [53] with compound [47].

Step 5

In the same manner as in production method 1-2-1, step 3, compound [55] can be obtained by converting the amino group of compound [54] to a leaving group.

Step 6

In the same manner as in production method 1-2, step 1, compound [I-19] can be obtained by reacting compound [55] with compound [I-1].

Step 7

Compound [I-19-1] can be obtained by introducing a substituent selected from group A into the nitrogen atom on compound [I-19] by a conventional method.

Compound [I-19-1] can also be obtained by performing the production methods of step 5 and step 6 using R^(A13)—NH—NH₂ instead of compound [47].

Production Method 1-2-6 Production Example of Compound [30] (R^(A6) is a Hydroxyl Group)

wherein R^(C24) and R^(C25) are the same or different and each is a carboxylic acid protecting group, and other symbols are as defined above.

Compound [30-1] can be obtained by reacting compound [56] with compound [57] in a methanol solvent under heating under reflux in the presence of sodium methoxide.

In addition, compound [30-1] can be obtained by reacting compound [58] with compound [59] in a solvent in the presence of a base.

As the solvent, dichloromethane, chloroform, THF, toluene and the like can be mentioned.

As the base, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene and the like can be mentioned.

Production Method 1-2-7 Production Example of Compound [43] and Compound [44]

wherein each symbol is as defined above.

Compound [43] can be obtained by halogenating compound [60] by a conventional method.

For example, compound [43] can be obtained by brominating compound [60] using copper(II) bromide and hydroxy(tosyloxy)iodobenzene in an acetonitrile solvent.

In addition, compound [44] can also be obtained by reacting compound [60] with hydroxy(tosyloxy)iodobenzene in an acetonitrile solvent under heating conditions, and then reacting the obtained compound with thiourea under heating conditions.

Production Method 1-2-8 Production Example of Compound [50]

wherein R^(C21) is a halogen atom such as a chlorine atom, a bromine atom and the like, and other symbols are as defined above.

Compound [50] can be obtained by reacting compound [61] with compound [62] in an alcohol solvent such as methanol, ethanol and the like or an ether solvent such as diethyl ether, THF and the like or a mixed solvent thereof in the presence of sodium methoxide.

R^(C21) is preferably a chlorine atom.

EXAMPLES

The compound represented by the formula [I] of the present invention and production methods thereof are explained in detail in the following by referring to Examples. However, the present invention is not limited by these Examples.

Example 1 Step 1 (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester

(R)-piperazine-2-carboxylic acid dihydrochloride (4.98 g) was suspended in a mixed solvent of 1,4-dioxane (50 ml) and water (25 ml) and, with stirring under ice-cooling, 50% aqueous sodium hydroxide solution (3.79 ml) and then di-tert-butyl dicarbonate (6.19 ml) were added. After stirring overnight at room temperature, triethylamine (6.83 ml), 4-trifluoromethylbenzenesulfonyl chloride (5.99 g) and 4-dimethylaminopyridine (60 mg) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and 1N aqueous hydrochloric acid solution. The aqueous layer was re-extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (9.16 g) containing the title compound as a main component.

Step 2 (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester

To a mixed solution of the compound (2.19 g) obtained in Step 1, 4-isopropylbenzylamine (761 mg) and 1-hydroxybenzotriazole hydrate (804 mg) in N,N-dimethylformamide (10 ml) was added, with stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.00 g). After stirring at room temperature for 3 days, the reaction mixture was partitioned by adding 1N aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (973 mg).

Step 3 (R)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide hydrochloride

To a solution of the compound (973 mg) obtained in Step 2 in ethyl acetate (10 ml) was added, with stirring at room temperature, 4N hydrogen chloride/ethyl acetate solution (4.73 ml). After stirring at room temperature for 4 hr, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in a mixed solvent of ethyl acetate and diisopropyl ether, collected by filtration and dried to give the title compound (742 mg).

Example 2 (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide

To a mixed solution of the compound (20 mg) obtained in Example 1,4-pyridylacetic acid hydrochloride (7.5 mg), 1-hydroxybenzotriazole hydrate (6.6 mg) and triethylamine (12 μl) in N,N-dimethylformamide (0.4 ml) was added, with stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.3 mg). After stirring overnight at room temperature, aqueous sodium hydrogen carbonate solution and methanol were added to the reaction mixture and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound (14 mg).

Example 3 (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide

To a solution of 4-aminopyridine (94 mg) in chloroform (2.0 ml) was added, with stirring at room temperature, N,N′-carbonyldiimidazole (178 mg), and the mixture was stirred overnight at room temperature to give the reaction mixture A.

In a separate container, to a solution of the compound (30 mg) obtained in Example 1 in chloroform (1 ml) was added, with stirring at room temperature, triethylamine (12.5 μl), the reaction mixture A (240 μl) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (10% methanol/chloroform) to give the title compound (31 mg).

Example 4 (R)-4-thiocarbamoyl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide

To a solution of the compound (506 mg) obtained in Example 1 in chloroform (5 ml) was added, with stirring at room temperature, triethylamine (167 μl), and 9-fluorenylmethoxycarbonyl isothiocyanate (281 mg) was added. After stirring overnight at room temperature, piperidine (198 μl) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography (3% methanol/chloroform) to give the title compound (442 mg).

Example 5 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid tert-butyl ester

A mixture of the compound (250 mg) obtained in Example 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (168 mg) in acetonitrile (1.25 ml) was stirred at 80° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (ethyl acetate:n-hexane=2:3) to give the title compound (268 mg).

Example 6 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid

A solution of the compound (224 mg) obtained in Example 5 in trifluoroacetic acid (1.1 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated again under reduced pressure. Diisopropyl ether was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, and dried to give the title compound (97 mg).

Example 7 (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide

To a solution of the compound (30 mg) obtained in Example 6 in tetrahydrofuran (0.3 ml) was added, with stirring at room temperature, N,N′-carbonyldiimidazole (10 mg). After stirring at room temperature for 3 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring at room temperature for 2.5 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring at room temperature for 2.5 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring overnight at room temperature, the reaction mixture was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (10% methanol/chloroform) to give the title compound (20 mg).

Example 8 (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester

A mixture of the compound (61 mg) obtained in Example 1, 5-chloropyrazine-2-carboxylic acid methyl ester (25 mg) and triethylamine (42 μl) in N,N-dimethylformamide (0.3 ml) was stirred at 60° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (5% methanol/chloroform) to give the title compound (75 mg).

Example 9 (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid

To a mixed solution of the compound (75 mg) obtained in Example 8 in tetrahydrofuran (400 μl) and methanol (400 μl) was added, with stirring at room temperature, 2N aqueous sodium hydroxide solution (186 μl). After stirring at room temperature for 30 min, 2N aqueous hydrochloric acid solution (186 μl) was added, and the mixture was concentrated under reduced pressure. Methanol and water were added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, and dried to give the title compound (61 mg).

Example 10 Step 1 (R)-4-acetyl-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester

(R)-piperazine-2-carboxylic acid dihydrochloride (5.0 g) was suspended in a mixed solvent of 1,4-dioxane (25 ml) and water (28 ml) and, with stirring under ice-cooling, 4N aqueous sodium hydroxide solution (22 ml) was added and a solution of p-nitrophenol acetate (4.69 g) in 1,4-dioxane (25 ml) was added dropwise over 30 min. After stirring at room temperature for 3 hr, the reaction mixture was concentrated under reduced pressure to evaporate 1,4-dioxane. The precipitated insoluble material was filtered off, and a solution of di-tert-butyl dicarbonate (8.5 ml) in 1,4-dioxane (30 ml) was added dropwise to the obtained filtrate (about 70 ml) with stirring under ice-cooling. After stirring at room temperature for 3 hr, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and diethyl ether. The aqueous layer was adjusted to pH 2 with 2N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure to give a crude product (4.83 g) containing the title compound as a main component.

Step 2 (R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester

To a mixed solution of the compound (4.83 g) obtained in Step 1, 4-isopropylbenzylamine (3.14 ml) and 1-hydroxybenzotriazole hydrate (2.64 g) in N,N-dimethylformamide (10 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.74 g). After stirring overnight at room temperature, the reaction mixture was partitioned by adding water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (methanol:chloroform=0:100→16:100) to give the title compound (4.72 g).

Step 3 (R)-4-acetyl-piperazine-2-carboxylic acid 4-isopropyl-benzylamide

To a solution of the compound (4.72 g) obtained in Step 2 in chloroform (5 ml) was added, with stirring at room temperature, 4N hydrogen chloride/1,4-dioxane solution (20 ml). After stirring at room temperature for 3 hr, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in diisopropyl ether, collected by filtration and dried to give the title compound (3.23 g).

Step 4 (R)-4-acetyl-1-(3-iodo-4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide

To a solution of the compound (40 mg) obtained in Step 3 and triethylamine (66 μl) in chloroform (0.4 ml) was added, with stirring at room temperature, 3-iodo-4-trifluoromethoxybenzenesulfonyl chloride (68 mg). After stirring at room temperature for 1 hr, the reaction mixture was directly purified by thin layer chromatography (methanol:chloroform=1:15) and recrystallized from water-containing methanol to give the title compound (53 mg).

Example 11 4-{5-[(R)-4-acetyl-2-(4-isopropyl-benzylcarbamoyl)-piperazine-1-sulfonyl]-2-trifluoromethoxy-phenyl}-butyric acid

Under an argon stream, to a suspension of the compound (46 mg) obtained in Example 10, 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (5 mg) and bis(dibenzylideneacetone)palladium(0) (4 mg) in tetrahydrofuran was added, with stirring under ice-cooling, 0.5M 4-ethoxy-4-oxobutylzinc bromide/tetrahydrofuran solution (422 μl). After stirring at room temperature for 24 hr, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtrated and concentrated under reduced pressure. Methanol (0.5 ml) was added to the residue, and 4N aqueous sodium hydroxide solution (35 μl) was added with stirring under ice-cooling. After stirring at room temperature for 3 hr, 2N aqueous hydrochloric acid solution (70 μl) was added, and the mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography (chloroform:methanol:acetic acid=90:10:1) and recrystallized from water-containing methanol to give the title compound (2.4 mg).

Example 12 Step 1 (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid

(R)-piperazine-2-carboxylic acid dihydrochloride (4.06 g) was suspended in a mixed solvent of 1,4-dioxane (20 ml) and water (20 ml), 4N aqueous sodium hydroxide solution (18 ml) was added, with stirring under ice-cooling, and a solution of p-nitrophenol acetate (3.99 g) in 1,4-dioxane (20 ml) was added dropwise. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to evaporate 1,4-dioxane. The precipitated insoluble material was filtered off, and washed with water. 1,4-Dioxane (40 ml) and triethylamine (5.57 ml) were added to the obtained filtrate, and 4-isopropylbenzenesulfonyl chloride (3.59 ml) was added dropwise with stirring under ice-cooling. After stirring overnight at room temperature, the reaction mixture was adjusted to pH 2 with 2N aqueous hydrochloric acid solution and 1,4-dioxane was evaporated by concentration under reduced pressure. The obtained aqueous solution was extracted 4 times with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude crystals were suspended in ethyl acetate, collected by filtration and dried to give a crude product (3.10 g) containing the title compound as a main component.

Step 2 (R)-4-acetyl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 2-methyl-4-propyl-benzylamide

To a mixed solution of the compound (35.4 mg) obtained in Step 1, 2-methyl-4-propylbenzylamine hydrochloride (22.0 mg), 1-hydroxybenzotriazole hydrate (18.4 mg) and triethylamine (17.4 μl) in N,N-dimethylformamide (0.2 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 mg). After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and chloroform. The organic layer was washed twice with water, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (methanol:chloroform=1:20) to give the title compound (40.5 mg).

Example 13 Step 1 (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester

(R)-piperazine-2-carboxylic acid dihydrochloride (5.08 g) was suspended in a mixed solvent of 1,4-dioxane (40 ml) and water (25 ml), 50% aqueous sodium hydroxide solution (3.87 ml) was added with stirring under ice-cooling, and a solution of di-tert-butyl dicarbonate (6.32 ml) in 1,4-dioxane (10 ml) was added dropwise. After stirring overnight at room temperature, triethylamine (6.97 ml), 4-trifluoromethoxybenzenesulfonyl chloride (4.24 ml) and 4-dimethylaminopyridine (61 mg) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to evaporate 1,4-dioxane. The residue was partitioned by adding ethyl acetate and 1N aqueous hydrochloric acid solution. The aqueous layer was re-extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (10.2 g) containing the title compound as a main component.

Step 2 (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester

To a mixed solution of the compound (5.77 g) obtained in Step 1, benzyl alcohol (1.45 ml) and 4-dimethylaminopyridine (77 mg) in chloroform (60 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.68 g). After stirring at room temperature for 3 hr, the mixture was concentrated under reduced pressure. The residue was partitioned by adding water and ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2) to give a crude product (3.66 g) containing the title compound as a main component.

Step 3 (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid benzyl ester hydrochloride

To a solution of the compound (3.66 g) obtained in Step 2 in ethyl acetate (10 ml) was added, with stirring at room temperature, 4N hydrogen chloride/ethyl acetate solution (16.8 ml). After stirring at room temperature for 4 hr, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product (2.58 g) containing the title compound as a main component.

Step 4 (R)-4-thiocarbamoyl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid benzyl ester

To a solution of the compound (2.58 g) obtained in Step 3 in chloroform (26 ml) was added, with stirring at room temperature, triethylamine (896 μl), and 9-fluorenylmethoxycarbonyl isothiocyanate (1.66 g) was added. After stirring overnight at room temperature, piperidine (1.11 ml) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography (5% methanol/chloroform) to give the title compound (2.12 g).

Step 5 (R)-4-(5-tert-butoxycarbonyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid benzyl ester

A mixture of the compound (2.12 g) obtained in Step 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (2.0 g) in acetonitrile (20 ml) was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer was washed successively with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (1.82 g).

Step 6 (R)-4-(5-tert-butoxycarbonyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid

A mixture of the compound (1.82 g) obtained in Step 5, 10% palladium carbon (250 mg) and acetic acid (4.0 ml) in methanol (50 ml) was stirred under a hydrogen atmosphere (4 atm) at room temperature for 3 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. 10% Palladium carbon (1.8 g), acetic acid (4.0 ml) and methanol (50 ml) were added again to the residue, and the mixture was stirred under a hydrogen atmosphere (4 atm) at room temperature for 30 min. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure (repeated 4 times). The obtained powder was suspended in water, collected by filtration and dried to give the title compound (1.24 g).

Step 7 2-[(R)-3-[(6-isopropyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid tert-butyl ester

To a mixed solution of the compound (55 mg) obtained in Step 6, [(6-isopropylpyridin-3-yl)methyl]amine (24 mg) and 1-hydroxybenzotriazole hydrate (23 mg) in N,N-dimethylformamide (660 μl) was added, with stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29 mg). After stirring at room temperature for 3 hr, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=3:2) to give the title compound (59 mg).

Step 8 2-[(R)-3-[(6-isopropyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid

A solution of the compound (55 mg) obtained in Step 7 in trifluoroacetic acid (330 μl) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, chloroform was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was purified by thin layer chromatography (methanol:chloroform=1:10) to give the title compound (43 mg).

Example 14 Step 1 (R)-piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester

(R)-piperazine-2-carboxylic acid dihydrochloride (10.0 g) was suspended in a mixed solvent of 1,4-dioxane (50 ml) and water (50 ml) and 50% aqueous sodium hydroxide solution (7.62 ml) was added with stirring under ice-cooling. After stirring under ice-cooling for 30 min, a solution of di-tert-butyl dicarbonate (11.8 g) in 1,4-dioxane (50 ml) was added dropwise. After stirring at room temperature for 7 hr, the reaction mixture was stirred again under ice-cooling, triethylamine (13.7 ml) was added, and benzyl chloroformate (7.03 ml) was added dropwise. After stirring overnight at room temperature, triethylamine (6.85 ml) and benzyl chloroformate (3.52 ml) were added. After stirring at room temperature for 4 hr, the mixture was concentrated under reduced pressure to evaporate 1,4-dioxane. The residue was adjusted to pH 5-6 with 0.5N aqueous hydrochloric acid solution, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and the insoluble material in the organic layer was filtered off. The filtrate was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (17.1 g) containing the title compound as a main component.

Step 2 (R)-2-(4-propyl-benzylcarbamoyl)-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester

To a mixed solution of the compound (3.41 g) obtained in Step 1, 4-n-propylbenzylamine hydrochloride (1.74 g) and 1-hydroxybenzotriazole hydrate (1.43 g) in N,N-dimethylformamide (34 ml) was added, with stirring at room temperature, triethylamine (1.96 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.80 g) was added. After stirring at room temperature for 4 hr, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=2:5) to give a crude product (2.64 g) containing the title compound as a main component.

Step 3 (R)-2-(4-propyl-benzylcarbamoyl)-piperazine-1-carboxylic acid benzyl ester

To the compound (2.64 g) obtained in Step 2 in 1,4-dioxane (13 ml) was added, with stirring at room temperature, 4N hydrogen chloride/1,4-dioxane (13 ml). After stirring at room temperature for 3 hr, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (5%-10% methanol/chloroform) to give the title compound (1.59 g).

Step 4 (R)-2-(4-propyl-benzylcarbamoyl)-4-thiocarbamoyl-piperazine-1-carboxylic acid benzyl ester

To a solution of the compound (1.59 g) obtained in Step 3 in chloroform (16 ml) was added, with stirring at room temperature, triethylamine (840 μl), and 9-fluorenylmethoxycarbonyl isothiocyanate (1.13 g) was added. After stirring at room temperature for 4 hr, piperidine (805 μl) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:1-4:1) to give the title compound (1.62 g).

Step 5 (R)-4-(5-tert-butoxycarbonyl-4-methyl-thiazol-2-yl)-2-(4-propyl-benzylcarbamoyl)-piperazine-1-carboxylic acid benzyl ester

A mixture of the compound (1.51 g) obtained in Step 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (1.58 g) in acetonitrile (15 ml) was stirred at 80° C. for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2-2:3) to give the title compound (1.29 g).

Step 6 4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-5-carboxylic acid tert-butyl ester

A mixture of the compound (1.00 g) obtained in Step 5 and 7.5% palladium carbon (1.0 g) in methanol (15 ml) was stirred under a hydrogen atmosphere (5 atm) at room temperature for 4 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. 10% Palladium carbon (500 mg) and methanol (15 ml) were added again to the residue, and the mixture was stirred under a hydrogen atmosphere (5 atm) at room temperature for 6 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (3%-5% methanol/chloroform) to give the title compound (688 mg).

Step 7 2-[(R)-4-(2-fluoro-4-trifluoromethoxy-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid tert-butyl ester

To a solution of the compound (50 mg) obtained in Step 6 in pyridine (0.5 ml) was added, with stirring at room temperature, 2-fluoro-4-trifluoromethoxybenzenesulfonyl chloride (46 mg). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate and water. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (59 mg).

Step 8 2-[(R)-4-(2-fluoro-4-trifluoromethoxy-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid

To a solution of the compound (59 mg) obtained in Step 7 in chloroform (0.3 ml) was added, with stirring at room temperature, trifluoroacetic acid (0.3 ml). After stirring at room temperature for 7 hr, the reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2-10% methanol/chloroform) to give the title compound (45 mg).

Example 783 Step 1 sodium (R)-4-tert-butoxycarbonyl-piperazine-2-carboxylate

(R)-piperazine-2-carboxylic acid dihydrochloride (20.0 g) was suspended in a mixed solvent of 1,4-dioxane (140 ml) and water (60 ml) and, with stirring under ice-cooling, 50% aqueous sodium hydroxide solution (15.2 ml) was added dropwise, and then a solution of di-tert-butyl dicarbonate (23.6 g) in 1,4-dioxane (60 ml) was added dropwise. The mixture was stirred under ice-cooling for 15 min, and the mixture was stirred at room temperature for 7 hr. Ethyl acetate (60 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration, washed with ethyl acetate (40 ml), and dried to give a crude product (13.3 g) containing the title compound as a main component.

¹H-NMR (D₂O, 400 MHz) δ: 1.49 (9H, s), 3.02-3.13 (1H, m), 3.21-3.44 (3H, m), 3.66-3.73 (1H, m), 3.89-4.12 (1H, br m), 4.28 (1H, dd, J=14.2, 4.1 Hz).

Step 2 (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester

The compound (6.8 g) obtained in Step 1 was suspended in a mixed solvent of 1,4-dioxane (68 ml) and water (20 ml) and, with stirring under ice-cooling, triethylamine (5.6 g) and 4-dimethylaminopyridine (66 mg) were added, and 4-trifluoromethoxybenzenesulfonyl chloride (7.4 g) was added dropwise. The mixture was stirred under ice-cooling for 20 min, and the mixture was stirred at room temperature for 5.5 hr. With stirring under ice-cooling again, the reaction mixture was adjusted to pH 3 by adding 2N aqueous hydrochloric acid solution (23.5 ml) and saturated aqueous sodium hydrogen carbonate solution (about 5 ml). Ethyl acetate (70 ml) and water (30 ml) were added. The reaction mixture was partitioned, and the aqueous layer was re-extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed twice with water (20 ml), washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (9.01 g) containing the title compound as a main component.

¹H-NMR (DMSO-d₆, 400 MHz) δ: 1.33 (9H, s), 2.66-2.87 (1H, br m), 3.03-3.17 (1H, br m), 3.21-3.31 (1H, m), 3.58-3.64 (1H, m), 3.83-3.99 (1H, br m), 4.31 (1H, d, J=13.9 Hz), 4.49 (1H, d, J=3.3 Hz), 7.56 (2H, d, J=8.9 Hz), 7.91 (2H, d, J=8.9 Hz), 13.05 (1H, s).

Step 3 (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of the compound (2.40 g) obtained in Step 2, 4-trifluoromethoxybenzylamine (1.21 g) and 1-hydroxybenzotriazole hydrate (1.21 g) in N,N-dimethylformamide (24 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.21 g). After stirring overnight at room temperature, and the reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude crystals were suspended in a mixed solution of diisopropyl ether and n-hexane, collected by filtration and dried to give the title compound (2.20 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.39 (9H, s), 2.60-3.10 (2H, br m), 3.31 (1H, m), 3.69 (1H, m), 3.84 (1H, d, J=14.0 Hz), 4.35-4.50 (3H, m), 4.56 (1H, d, J=13.6 Hz), 6.83 (1H, br s), 7.18 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.35 (2H, d, J=8.7 Hz), 7.91 (2H, d, J=8.7 Hz).

Step 4 (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

4N Hydrogen chloride/1,4-dioxane solution (40 ml) was added to the compound (2.20 g) obtained in Step 3, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium carbonate, filtrated, and concentrated under reduced pressure. The residue was crystallized from a mixed solvent of diisopropyl ether and n-hexane, collected by filtration and dried to give the title compound (1.57 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 2.45-2.58 (2H, m), 2.86 (1H, d, J=13.2 Hz), 3.16 (1H, dt, J=3.3, 6.8 Hz), 3.54 (1H, d, J=12.9 Hz), 3.76 (1H, d, J=13.7 Hz), 4.35 (1H, d, J=3.9 Hz), 4.40-4.55 (2H, m), 7.18 (2H, d, J=8.1 Hz), 7.20 (1H, m), 7.28 (2H, d, J=8.9 Hz), 7.35 (2H, d, J=8.1 Hz), 7.90 (2H, d, J=8.9 Hz).

Example 975 Step 1 6-amino-2-cyclopropyl-pyrimidin-4-ol

A mixed solution of cyclopropanecarboxamidine hydrochloride (0.30 g), ethyl cyanoacetate (0.27 ml) and methanol (1.5 ml) was added to 28% sodium methoxide methanol solution (2.0 ml) under ice-cooling. After heating under reflux for 1 hr, the mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was adjusted to pH 5 with water and acetic acid. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.30 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 0.91 (4H, d, J=6.0 Hz), 1.73-1.81 (1H, m), 4.79 (1H, s), 6.21 (2H, s), 11.53 (1H, br s).

Step 2 6-amino-2-cyclopropyl-5-thiocyanato-pyrimidin-4-ol

To a mixed solution of the compound (0.30 g) obtained in Step 1, potassium thiocyanate (0.77 g) and N,N-dimethylformamide (6.0 ml) was added pyridine (0.29 ml) at 90° C. After allowing to cool to 40° C., a mixed solution of bromine (0.15 ml) and N,N-dimethylformamide (1.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. Under ice-cooling, water (12 ml) was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.40 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 0.97-1.05 (4H, m), 1.76-1.87 (1H, m), 7.42 (2H, br s), 12.21 (1H, br s).

Step 3 2-amino-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-7-ol

A solution of the compound (0.20 g) obtained in Step 2 in N,N-dimethylformamide (7.0 ml) was stirred overnight under heating at 135° C. The reaction mixture was cooled to room temperature, and water (7.0 ml) was added under ice-cooling. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.15 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 0.96-1.03 (4H, m), 1.88-1.98 (1H, m), 8.02 (2H, s), 12.40 (1H, br s).

Step 4 2-chloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-7-ol

The compound (1.2 g) obtained in Step 3 was suspended in 2N aqueous sodium hydroxide solution (18 ml) and, under ice-cooling, sodium nitrite (1.2 g) was added in several portions. The obtained suspension was slowly added dropwise to a concentrated aqueous hydrochloric acid solution (18 ml) heated to 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.60 g). The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (0.34 g) containing the title compound as a main component. The obtained crude crystals were suspended in a mixed solvent of hexane and ethyl acetate, collected by filtration and dried to give the title compound (0.26 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 1.08-1.13 (4H, m), 2.01-2.06 (1H, m), 13.15 (1H, br s).

Step 5 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine

To a solution of the compound (0.82 g) obtained in Step 4 in phosphorus oxychloride (2.5 ml) was added N,N-diisopropylethylamine (0.25 ml) under ice-cooling, and the mixture was heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained residue was dissolved in ethyl acetate, poured into ice water and partitioned. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:8) to give the title compound (0.79 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.15-1.31 (4H, m), 2.32-2.43 (1H, m).

Step 6 (R)-4-(7-chloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixed solution of the compound (0.94 g) obtained in Example 783, the compound (0.48 g) obtained in Step 5 and chloroform (2.8 ml) was added N,N-diisopropylethylamine (0.30 ml) at room temperature. The mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound (1.3 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.03-1.24 (4H, m), 2.16-2.28 (1H, m), 3.11-3.37 (2H, m), 3.39-3.54 (1H, m), 3.92 (1H, d, J=14.3 Hz), 4.23-4.60 (4H, m), 4.64 (1H, s), 6.90 (1H, t, J=5.8 Hz), 7.12 (2H, d, J=8.3 Hz), 7.21 (2H, d, J=8.7 Hz), 7.37 (2H, d, J=8.3 Hz), 7.93 (2H, d, J=8.7 Hz).

Step 7 (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixed solution of the compound (1.3 g) obtained in Step 6, ammonium formate (1.2 g) and ethanol (13 ml) was added 10% palladium carbon (1.3 g) at 80° C. After stirring at the same temperature for 30 min, ammonium formate (1.3 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, ammonium formate (1.2 g) and 10% palladium carbon (0.65 g) were further added. After stirring at the same temperature for 1.5 hr, the reaction mixture was allowed to return to room temperature and diluted with chloroform. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound (0.91 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.01-1.09 (2H, m), 1.16-1.21 (2H, m), 2.21-2.30 (1H, m), 3.12-3.36 (2H, m), 3.42-3.51 (1H, m), 3.91 (1H, d, J=13.6 Hz), 4.24-4.52 (3H, m), 4.55-4.67 (2H, m), 6.90-6.98 (1H, m), 7.09 (2H, d, J=9.0 Hz), 7.19 (2H, d, J=8.7 Hz), 7.36 (2H, d, J=8.7 Hz), 7.93 (2H, d, J=8.7 Hz), 8.61 (1H, s).

Example 1001 Step 1 (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester

Sodium (R)-4-tert-butoxycarbonyl-piperazine-2-carboxylate (10.0 g) was suspended in a mixed solvent of 1,4-dioxane (100 ml) and water (30 ml) and, with stirring under ice-cooling, triethylamine (11.3 ml) and 4-dimethylaminopyridine (97 mg) were added, and 4-trifluoromethylbenzenesulfonyl chloride (10.2 g) was added dropwise. After stirring overnight at room temperature, 2N aqueous hydrochloric acid solution was added with stirring under ice-cooling to adjust the reaction mixture to pH 3, and ethyl acetate and water were added. The reaction mixture was partitioned, the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (10.2 g) containing the title compound as a main component.

¹H-NMR (DMSO-d₆, 400 MHz) δ: 1.32 (9H, s), 2.68-2.87 (1H, m), 3.01-3.17 (1H, m), 3.25 (1H, d, J=13.6 Hz), 3.64 (1H, d, J=10.2 Hz), 3.84-4.03 (1H, m), 4.32 (1H, d, J=13.6 Hz), 4.51 (1H, s), 7.97 (4H, s), 13.08 (1H, s).

Step 2 (R)-3-(4-difluoromethoxy-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of the compound (1.00 g) obtained in Step 1, 4-difluoromethoxybenzylamine (474 mg) and 1-hydroxybenzotriazole hydrate (420 mg) in N,N-dimethylformamide (10 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (524 mg). After stirring overnight at room temperature, the reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude crystals were suspended in a mixed solution of diisopropyl ether and n-hexane, collected by filtration and dried to give the title compound (956 mg).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 1.39 (9H, s), 2.60-3.20 (2H, br m), 3.20-3.40 (1H, m), 3.65-3.80 (1H, m), 3.86 (1H, d, J=13.6 Hz), 4.35-4.55 (3H, m), 4.56 (1H, d, J=14.0 Hz), 6.50 (1H, t, J=73.8 Hz), 6.77 (1H, br s), 7.09 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 7.79 (2H, d, J=8.3 Hz), 7.98 (2H, d, J=8.3 Hz).

Step 3 (R)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide

4N Hydrogen chloride/1,4-dioxane solution (20 ml) was added to the compound (950 mg) obtained in Step 2, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium carbonate, filtrated, and concentrated under reduced pressure to give a crude product (807 mg) containing the title compound as a main component.

¹H-NMR (CDCl₃, 300 MHz) δ: 2.45-2.60 (2H, m), 2.87 (1H, d, J=12.4 Hz), 3.18 (1H, dt, J=3.3, 13.1 Hz), 3.53 (1H, d, J=12.7 Hz), 3.77 (1H, d, J=13.3 Hz), 4.35-4.50 (3H, m), 6.50 (1H, t, J=73.8 Hz), 7.08 (2H, d, J=8.5 Hz), 7.19 (1H, br s), 7.24 (2H, d, J=8.5 Hz), 7.80 (2H, d, J=8.4 Hz), 7.98 (2H, d, J=8.4 Hz).

Step 4 6-amino-2-trifluoromethyl-pyrimidin-4-ol

Under stirring at room temperature, malonamidine hydrochloride (406 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (870 ml) were added to tetrahydrofuran (2 L), and ethyl trifluoroacetate (1040 ml) was added dropwise. After stirring under heating at a bath temperature of 65° C. for 17.5 hr, water (200 ml) was added, and the reaction mixture was concentrated. Water (1 L) was added to the concentrated residue, concentrated hydrochloric acid (485 ml) was added dropwise with stirring at room temperature and the mixture was stirred for 1 hr. After cooling the inside temperature to 0° C. or below, the precipitated crystals were collected by filtration, washed twice with water (600 ml), and dried to give the title compound (251 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 5.68 (1H, s), 7.10 (2H, br s), 11.64 (1H, br s).

Step 5 6-amino-5-thiocyanato-2-trifluoromethyl-pyrimidin-4-ol

To a solution of potassium thiocyanate (6.78 g) and pyridine (3.37 ml) in N,N-dimethylformamide (75 ml) was added dropwise bromine (1.72 ml) with stirring under ice-cooling. After stirring under ice-cooling for 1 hr, a solution of the compound (5.00 g) obtained in Step 4 in N,N-dimethylformamide (25 ml) was added dropwise. After further stirring under ice-cooling for 1 hr, water was added, and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (4.40 g) containing the title compound as a main component.

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.17 (2H, br s), 13.58 (1H, br s).

Step 6 2-amino-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-7-ol

A solution of the compound (4.25 g) obtained in Step 5 in N,N-dimethylformamide (128 ml) was stirred at 130° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, xylene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in ethyl acetate, collected by filtration and dried to give the title compound (3.35 g).

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.58 (2H, s).

Step 7 2-chloro-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-7-ol

To a solution of the compound (3.00 g) obtained in Step 6 in 6N hydrochloric acid (45 ml) was added sodium nitrite (8.76 g) in several portions with stirring at room temperature, and the mixture was further stirred at room temperature for 30 min. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound (1.46 g).

Step 8 2,7-dichloro-5-trifluoromethyl-thiazolo[4,5-d]pyrimidine

To a solution of the compound (1.35 g) obtained in Step 7 in phosphorus oxychloride (20 ml) was added water (190 mg) with stirring under ice-cooling, and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and partitioned by adding chloroform and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (1.17 g).

Step 9 (R)-4-(7-chloro-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide

To a solution of the compound (700 mg) obtained in Step 3 and N,N-diisopropylethylamine (371 mg) in chloroform (11 ml) was added the compound (389 mg) obtained in Step 8 with stirring under ice-cooling. After stirring at room temperature for 1 hr, the reaction mixture was partitioned by adding chloroform and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (1.09 g) containing the title compound as a main component.

¹H-NMR (CDCl₃, 300 MHz) δ: 3.45-3.48 (3H, m), 3.99 (1H, d, J=13.9 Hz), 4.44-4.59 (5H, m), 6.49 (1H, t, J=73.5 Hz), 6.81 (1H, t, J=10.0 Hz), 7.03 (2H, d, J=8.7 Hz), 7.18 (2H, d, J=8.3 Hz), 7.84 (2H, d, J=8.7 Hz), 8.02 (2H, d, J=8.3 Hz).

Step 10 (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide

Under a nitrogen atmosphere, to a solution of the compound (1.09 g) obtained in Step 9 and ammonium formate (895 mg) in ethanol (15 ml)-methanol (5 ml) was added 10% palladium carbon (1.0 g). After stirring at 85° C. for 1 hr, the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (596 mg).

¹H-NMR (CDCl₃, 400 MHz) δ: 3.34-3.50 (3H, m), 3.98 (1H, d, J=14.1 Hz), 4.42-4.58 (5H, m), 6.47 (1H, t, J=73.7 Hz), 6.88 (1H, t, J=10.0 Hz), 7.00 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.6 Hz), 7.82 (2H, d, J=8.4 Hz), 8.01 (2H, d, J=8.2 Hz), 8.87 (1H, s).

Example 983 Step 1 (R)-3-(4-trifluoromethoxy-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of the compound (2.98 g) obtained in Example 1001, Step 1, 4-trifluoromethoxybenzylamine (1.56 g) and 1-hydroxybenzotriazole hydrate (1.25 g) in N,N-dimethylformamide (30 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.56 g) with stirring under ice-cooling. After stirring overnight at room temperature, the reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude crystals were suspended in a mixed solution of diisopropyl ether and n-hexane, collected by filtration and dried to give the title compound (2.79 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.39 (9H, s), 2.60-3.20 (2H, br m), 3.20-3.40 (1H, br m), 3.65-3.80 (1H, br m), 3.86 (1H, d, J=13.3 Hz), 4.35-4.55 (3H, m), 4.56 (1H, d, J=14.0 Hz), 6.80 (1H, br s), 7.18 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4 Hz), 7.99 (2H, d, J=8.4 Hz).

Step 2 (R)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

4N Hydrogen chloride/1,4-dioxane solution (30 ml) was added to the compound (2.78 g) obtained in Step 1, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium carbonate, filtrated, and concentrated under reduced pressure to give a crude product (2.31 g) containing the title compound as a main component.

¹H-NMR (CDCl₃, 300 MHz) δ: 2.45-2.56 (2H, m), 2.87 (1H, d, J=13.0 Hz), 3.17 (1H, dt, J=3.2, 13.1 Hz), 3.53 (1H, d, J=12.9 Hz), 3.78 (1H, d, J=11.6 Hz), 4.38 (1H, d, J=3.9 Hz), 4.38-4.53 (2H, m), 7.18 (2H, d, J=8.5 Hz), 7.23 (1H, br s), 7.27 (2H, d, J=8.5 Hz), 7.80 (2H, d, J=8.4 Hz), 7.98 (2H, d, J=8.4 Hz).

Step 3 (R)-4-(7-chloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixed solution of the compound (0.75 g) obtained in Step 2 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (0.36 g) in chloroform (7.5 ml) was added at room temperature N,N-diisopropylethylamine (0.31 ml). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3-3:2) to give the title compound (0.99 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.03-1.10 (2H, m), 1.17-1.22 (2H, m), 2.17-2.27 (1H, m), 3.13-3.35 (2H, m), 3.42-3.53 (1H, m), 3.94 (1H, d, J=13.9 Hz), 4.23-4.38 (2H, m), 4.48 (1H, dd, J=15.1, 6.0 Hz), 4.54-4.68 (2H, m), 6.88 (1H, t, J=5.8 Hz), 7.12 (2H, d, J=8.3 Hz), 7.21 (2H, d, J=8.3 Hz), 7.82 (2H, d, J=8.3 Hz), 8.01 (2H, d, J=7.9 Hz).

Step 4 (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixture of the compound (0.99 g) obtained in Step 3 and ammonium formate (0.86 g) in ethanol (10 ml) was added 10% palladium carbon (0.50 g) at 80° C. After stirring at 80° C. for 30 min, ammonium formate (0.43 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, ammonium formate (0.43 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=7:3-8:2) to give the title compound (0.71 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.03-1.08 (2H, m), 1.17-1.21 (2H, m), 2.22-2.29 (1H, m), 3.21 (1H, t, J=10.9 Hz), 3.32 (1H, d, J=11.6 Hz), 3.46-3.53 (1H, m), 3.90-3.98 (1H, m), 4.22-4.52 (3H, m), 4.59-4.73 (2H, m), 7.00 (1H, t, J=5.9 Hz), 7.09 (2H, d, J=8.1 Hz), 7.19 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.3 Hz), 8.01 (2H, d, J=8.3 Hz), 8.62 (1H, s).

Example 1061 Step 1 4-difluoromethoxy-3-fluoro-benzonitrile

To a mixed solution of 3-fluoro-4-hydroxybenzonitrile (3.10 g) in N,N-dimethylformamide (31 ml)/water (3.1 ml) were successively added cesium carbonate (10.3 g) and sodium chlorodifluoroacetate (7.93 g). After stirring at 110° C. for 2 hr, the reaction mixture was partitioned by adding toluene and water. The aqueous layer was extracted with toluene, and the combined organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (4.09 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 6.64 (1H, t, J=72.0 Hz), 7.34-7.41 (1H, m), 7.45-7.53 (2H, m).

Step 2 (4-difluoromethoxy-3-fluoro-benzyl)-carbamic acid tert-butyl ester

Under an argon atmosphere, to a solution of the compound (4.09 g) obtained in Step 1 in methanol (30 ml) were added a solution of di-tert-butyl dicarbonate (10.5 g) in methanol (10 ml) and nickel(II) chloride hexahydrate (520 mg). With stirring under ice-cooling, sodium borohydride (4.96 g) was added by small portions over about 30 min, and methanol (8 ml) was added. After stirring overnight at room temperature, diethylenetriamine (5.2 ml) and methanol (8 ml) were added. After stirring for 1 hr, the reaction mixture was concentrated. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the residue and, after stirring at room temperature for 1 hr, the mixture was partitioned. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=10:1-4:1) to give the title compound (4.52 g).

¹H-NMR (CDCl₃, 400 MHz) δ: 1.46 (9H, s), 4.29 (2H, d, J=6.0 Hz), 4.89 (1H, br s), 6.52 (1H, t, J=73.6 Hz), 7.04 (1H, d, J=8.4 Hz), 7.11 (1H, dd, J=11.0, 2.0 Hz), 7.19 (1H, t, J=8.0 Hz).

Step 3 4-difluoromethoxy-3-fluoro-benzylamine

To a solution of the compound (4.52 g) obtained in Step 2 in 1,4-dioxane (5 ml) was added 4N hydrogen chloride/1,4-dioxane (15 ml) solution, and the mixture was stirred at room temperature for 1 hr. Diisopropyl ether (40 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration, washed with diisopropyl ether, and dried to give a white solid (2.80 g). With stirring under ice-cooling, the obtained white solid was suspended in ethyl acetate, and neutralized with aqueous sodium hydrogen carbonate solution. After partitioning, the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (2.03 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 3.87 (2H, s), 6.53 (1H, t, J=73.7 Hz), 7.07 (1H, d, J=8.3 Hz), 7.14-7.23 (2H, m).

Step 4 (R)-3-(4-difluoromethoxy-3-fluoro-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of the compound (1.83 g) obtained in Example 783, Step 2 in N,N-dimethylformamide (10 ml) were successively added, with stirring under ice-cooling, 1-hydroxybenzotriazole hydrate (677 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (847 mg) and a solution of 4-difluoromethoxy-3-fluorobenzylamine (806 mg) in N,N-dimethylformamide (3 ml). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (2.76 g).

Step 5 (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide

To a solution of the compound (2.76 g) obtained in Step 4 in ethyl acetate (4 ml) was added 4N hydrogen chloride/ethyl acetate solution (20 ml), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (1.94 g) containing the title compound as a main component.

¹H-NMR (CDCl₃, 400 MHz) δ: 2.46-2.59 (2H, m), 2.86 (1H, d, J=13.0 Hz), 3.13-3.21 (1H, m), 3.53 (1H, d, J=13.0 Hz), 3.76 (1H, d, J=13.9 Hz), 4.32-4.50 (3H, m), 6.54 (1H, t, J=73.4 Hz), 7.01 (1H, d, J=8.4 Hz), 7.08 (1H, dd, J=10.9, 2.1 Hz), 7.19 (1H, t, J=8.2 Hz), 7.28 (1H, br s), 7.36 (2H, d, J=8.2 Hz), 7.91 (2H, dt, J=9.3, 2.4 Hz).

Step 6 (R)-4-(7-chloro-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide

To a solution of the compound (796 mg) obtained in Step 5 in chloroform (8 ml) were successively added, with stirring under ice-cooling, N,N-diisopropylethylamine (234 mg) and 2,7-dichloro-5-trifluoromethyl-thiazolo[4,5-d]pyrimidine (414 mg). After stirring at room temperature for 1 hr, the mixture was partitioned by adding chloroform and water. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=6:1-1:2) to give the title compound (912 mg).

Step 7 (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide

Under an argon atmosphere, to a solution of the compound (912 mg) obtained in Step 6 and ammonium formate (750 mg) in ethanol (18 ml) was added 10% palladium carbon (912 mg). After stirring under refluxing conditions for 1 hr, the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and water. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=10:1-1:2) to give the title compound (625 mg).

¹H-NMR (CDCl₃, 400 MHz) δ: 3.16-3.42 (2H, m), 3.47 (1H, t, J=12.4 Hz), 3.97 (1H, d, J=14.3 Hz), 4.22-4.77 (2H, br m), 4.28 (1H, dd, J=15.1, 5.4 Hz), 4.48 (1H, dd, J=15.1, 6.7 Hz), 4.68 (1H, d, J=2.4 Hz), 6.51 (1H, t, J=73.3 Hz), 6.93-7.00 (3H, m), 7.13 (1H, t, J=8.0 Hz), 7.39 (2H, d, J=8.2 Hz), 7.95 (2H, dt, J=9.4, 2.4 Hz), 8.88 (1H, s).

Example 1101 Step 1 (3-fluoro-4-trifluoromethoxy-phenyl)-methanol

To a solution of 3-fluoro-4-trifluoromethoxybenzaldehyde (3.00 g) in THF (15 ml) was added, with stirring under ice-cooling, sodium borohydride (655 mg). After stirring at room temperature for 1 hr, the mixture was partitioned by adding ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (2.99 g) containing the title compound as a main component.

¹H-NMR (CDCl₃, 300 MHz) δ: 1.80 (1H, t, J=5.8 Hz), 4.71 (2H, d, J=5.3 Hz), 7.14 (1H, d, J=8.3 Hz), 7.23-7.32 (2H, m).

Step 2 2-(3-fluoro-4-trifluoromethoxy-benzyl)-isoindole-1,3-dione

To a solution of the compound (2.95 g) obtained in Step 1 in THF (30 ml) were added phthalimide (3.10 g) and triphenylphosphine (5.52 g) with stirring at room temperature, and the mixture was stirred under ice-cooling. With stirring under ice-cooling, diisopropyl azodicarboxylate (4.15 ml) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:8-3:7) to give the title compound (4.30 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 4.83 (2H, s), 7.21-7.31 (3H, m), 7.71-7.77 (2H, m), 7.84-7.90 (2H, m).

Step 3 3-fluoro-4-trifluoromethoxy-benzylamine

To a suspension of the compound (4.30 g) obtained in Step 2 in ethanol (65 ml) was added hydrazine monohydrate (1.84 ml) at room temperature. With heating under reflux, the mixture was stirred for 1 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product (1.28 g) containing the title compound as a main component.

¹H-NMR (CDCl₃, 300 MHz) δ: 1.48 (2H, br s), 3.89 (2H, s), 7.11 (1H, d, J=8.3 Hz), 7.19-7.29 (2H, m).

Step 4 (R)-3-(3-fluoro-4-trifluoromethoxy-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of the compound (1.24 g) obtained in Example 1001, Step 1 in N,N-dimethylformamide (12 ml) were added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.65 g), 1-hydroxybenzotriazole hydrate (0.52 g) and the compound (0.59 g) obtained in Step 3. After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=4:96-6:94) to give the title compound (1.70 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.38 (9H, s), 2.63-3.12 (3H, m), 3.20-3.37 (1H, m), 3.64-3.79 (1H, m), 3.87 (1H, d, J=13.6 Hz), 4.32-4.62 (3H, m), 6.93 (1H, t, J=6.6 Hz), 7.02-7.13 (2H, m), 7.24-7.29 (1H, m), 7.81 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.7 Hz).

Step 5 (R)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzylamide hydrochloride

To a solution of the compound (60 mg) obtained in Step 4 in 1,4-dioxane (0.6 ml) was added 4N hydrogen chloride/1,4-dioxane solution (0.6 ml) with stirring at room temperature. After stirring at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure to give a crude product (about 0.095 mmol) containing the title compound as a main component. The obtained crude product was directly used for the next reaction.

Step 6 (R)-4-(7-chloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzylamide

To a mixture of the crude product (about 0.095 mmol) obtained in Step 5 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (24 mg) in chloroform (1.0 ml) was added N,N-diisopropylethylamine (42 μl) at room temperature. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:10) to give the title compound (52 mg).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.03-1.09 (2H, m), 1.17-1.22 (2H, m), 2.18-2.27 (1H, m), 3.14-3.35 (2H, m), 3.43-3.53 (1H, m), 3.96 (1H, d, J=13.6 Hz), 4.22-4.36 (2H, m), 4.45-4.69 (3H, m), 6.97-7.06 (3H, m), 7.20 (1H, t, J=8.5 Hz), 7.83 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz),

Step 7 (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzylamide

To a mixture of the compound (49 mg) obtained in Step 6 and ammonium formate (42 mg) in ethanol (1.0 ml) was added 10% palladium carbon (25 mg) at 80° C. After stirring at 80° C. for 30 min, 10% palladium carbon (25 mg) was added. After stirring at 80° C. for 30 min, ammonium formate (42 mg) and 10% palladium carbon (25 mg) were added. After stirring at 80° C. for 30 min, 10% palladium carbon (25 mg) was added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:10) to give the title compound (29 mg).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.02-1.08 (2H, m), 1.15-1.20 (2H, m), 2.20-2.29 (1H, m), 3.16-3.27 (1H, m), 3.29-3.37 (1H, m), 3.44-3.54 (1H, m), 3.95 (1H, d, J=13.9 Hz), 4.20-4.33 (2H, m), 4.50 (1H, dd, J=15.3, 6.6 Hz), 4.59-4.71 (2H, m), 6.94-7.04 (2H, m), 7.08 (1H, t, J=5.8 Hz), 7.16 (1H, t, J=7.5 Hz), 7.82 (2H, d, J=8.7 Hz), 8.02 (2H, d, J=8.3 Hz), 8.61 (1H, s).

Example 1102 Step 1 (R)-3-(3-fluoro-4-trifluoromethoxy-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of the compound (1.35 g) obtained in Example 783, Step 2 in chloroform (15 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (625 mg), 1-hydroxybenzotriazole hydrate (499 mg) and 3-fluoro-4-trifluoromethoxybenzylamine (620 mg) with stirring under ice-cooling. After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and chloroform, and the aqueous layer was re-extracted twice with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (1.50 g).

Step 2 (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzylamide

After stirring the compound (1.50 g) obtained in Step 1 in 4N hydrogen chloride/1,4-dioxane solution (20 ml) at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure. The residue was partitioned by adding chloroform and saturated aqueous sodium hydrogen carbonate solution and the aqueous layer was re-extracted twice with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (1.36 g) containing the title compound as a main component. A part thereof was used for the next reaction.

¹H-NMR (CDCl₃, 400 MHz) δ: 2.46-2.58 (2H, m), 2.87 (1H, d, J=11.6 Hz), 3.12-3.22 (1H, m), 3.54 (1H, d, J=12.8 Hz), 3.74-3.81 (1H, m), 4.34-4.52 (3H, m), 7.01-7.14 (2H, m), 7.29-7.40 (3H, m), 7.92 (2H, dt, J=9.4, 2.5 Hz).

Step 3 (R)-4-(7-chloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzylamide

To a solution of the crude product (38 mg) obtained in Step 2 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (18 mg) in chloroform (1.0 ml) was added at room temperature N,N-diisopropylethylamine (15 μl). After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure to give a crude product (about 0.070 mmol) containing the title compound as a main component. The crude product was directly used for the next reaction.

Step 4 (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzylamide

To a solution of the compound (about 0.070 mmol) obtained in Step 3 and a large excess of ammonium formate in ethanol (2.0 ml) was added, with heating under reflux, 10% palladium carbon (25 mg). Thereafter, 10% palladium carbon (25 mg) was added twice every 10 min with heating under reflux. The mixture was heated under reflux for 30 min in total, and the reaction mixture was allowed to return to room temperature, and diluted with chloroform. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned by adding chloroform and water, and the organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:20) to give the title compound (21 mg).

¹H-NMR (CDCl₃, 400 MHz) δ: 1.01-1.08 (2H, m), 1.15-1.21 (2H, m), 2.25 (1H, tt, J=8.1, 3.9 Hz), 3.15-3.37 (2H, m), 3.43-3.53 (1H, m), 3.92 (1H, dt, J=14.1, 3.1 Hz), 4.21-4.69 (5H, m), 6.96 (1H, d, J=8.3 Hz), 7.03 (1H, dd, J=10.3, 2.0 Hz), 7.08-7.21 (2H, m), 7.37 (2H, d, J=8.1 Hz), 7.94 (2H, dt, J=9.5, 2.4 Hz), 8.62 (1H, s).

Example 574 Step 1 (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide

To a solution of the compound (6.65 g) obtained in Example 783, Step 2, 4-propylbenzylamine (3.26 g) and 1-hydroxybenzotriazole hydrate (2.69 g) in N,N-dimethylformamide (33 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.37 g). After stirring overnight at room temperature, saturated aqueous sodium hydrogen carbonate solution and water were added under ice-cooling, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a crude product (7.40 g). This was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give a crude product containing (R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as a main component. The obtained crude product was dissolved in 1,4-dioxane (40 ml), 4N hydrogen chloride/1,4-dioxane solution (50 ml) was added at room temperature, and the mixture was stirred at room temperature for 2 hr. Further, 4N hydrogen chloride/1,4-dioxane solution (20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl-acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium carbonate, filtrated, and concentrated under reduced pressure to give a crude product (3.70 g) containing the title compound as a main component. The residue was crystallized from a mixed solvent of diisopropyl ether and n-hexane, and collected by filtration. The obtained crude crystals were suspended in diisopropyl ether, collected by filtration and dried to give the title compound (3.0 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 0.94 (3H, t, J=7.3 Hz), 1.58-1.71 (2H, m), 2.48-2.63 (4H, m), 2.86 (1H, d, J=12.1 Hz), 3.11-3.24 (1H, m), 3.53 (1H, d, J=13.2 Hz), 3.74 (1H, d, J=12.4 Hz), 4.34 (1H, d, J=4.1 Hz), 4.40 (2H, d, J=5.7 Hz), 6.97-7.05 (1H, br m), 7.14 (4H, s), 7.33 (2H, d, J=8.3 Hz), 7.89 (2H, d, J=8.7 Hz).

Step 2 puteridin-7-ol

To a mixed solution of pyrimidine-4,5-diamine (4.4 g), sodium acetate (6.1 g), water (40 ml) and 5N aqueous acetic acid solution (10 ml) was added methyl 2-hydroxy-2-methoxyacetate (7.2 g) at 90° C. and the mixture was stirred under heating at the same temperature for 1 hr. The reaction mixture was cooled to room temperature, and adjusted to pH 2 with 5N aqueous sulfuric acid solution (9.0 ml). The precipitated solid was collected by filtration, washed with water and dried to give the title compound (4.7 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 8.26 (1H, s), 8.99 (1H, s), 9.13 (1H, s), 13.20 (1H, br s).

Step 3 7-chloro-puteridine

A mixed solution of the compound (0.50 g) obtained in Step 2 and pentachloroethane (27.5 ml) was heated under reflux. Phosphorus pentachloride (8.7 g) was added, and the mixture was heated under reflux for 15 min. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration, and dried to give the title compound (0.42 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 9.28 (1H, s), 9.61 (1H, s), 9.88 (1H, s).

Step 4 (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide

To a mixed solution of the compound (0.050 g) obtained in Step 1, the compound (0.034 g) obtained in Step 3 and isopropanol (1.0 ml) was added triethylamine (0.016 ml) at room temperature and the mixture was heated under reflux for 3.5 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, water was poured, and the mixture was partitioned. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol:ethyl acetate=1:20) and the obtained residue was suspended in a mixed solvent of hexane and diisopropyl ether, collected by filtration and dried to give the title compound (0.026 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 0.91 (3H, t, J=7.3 Hz), 1.51-1.65 (2H, m), 2.50 (2H, t, J=7.7 Hz), 2.92-3.07 (1H, m), 3.20 (1H, dd, J=13.6, 3.4 Hz), 3.36-3.50 (1H, m), 3.90-4.00 (1H, m), 4.25-4.38 (2H, m), 4.66 (1H, s), 4.77-4.90 (1H, m), 5.08 (1H, d, J=13.6 Hz), 6.82 (1H, t, J=5.3 Hz), 6.97 (2H, d, J=8.3 Hz), 7.00 (2H, d, J=8.3 Hz), 7.37 (2H, d, J=8.3 Hz), 7.95 (2H, d, J=8.3 Hz), 8.79 (1H, s), 9.22 (1H, s), 9.26 (1H, s).

Example 805 Step 1 2-bromo-4-methoxy-3-oxo-butyric acid methyl ester

Copper(II) bromide (7.37 g) was suspended in acetonitrile (39 ml), and 4-methoxy-3-oxobutyric acid methyl ester (3.88 ml, 30 mmol) and hydroxy(tosyloxy)iodobenzene (11.8 g) were added with stirring under ice-cooling. The reaction mixture was directly stirred for 3 hr, and water and chloroform were added. The reaction mixture was partitioned, and the aqueous layer was re-extracted twice with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (about 30 mmol) containing the title compound as a main component. The obtained crude product was directly used for the next reaction.

Step 2 2-amino-4-methoxymethylthiazole-5-carboxylic acid methyl ester

A solution of the crude product (about 30 mmol) obtained in Step 1 and thiourea (2.28 g) in ethanol (60 ml) was heated under reflux overnight. After cooling to room temperature, the reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. Then, suitable amounts of isopropanol, chloroform, ethyl acetate and diisopropyl ether were added, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration and dried to give the title compound (3.27 g).

¹H-NMR (CDCl₃, 400 MHz) δ: 3.47 (3H, s), 3.81 (3H, s), 4.74 (2H, s), 5.45 (2H, br s).

Step 3 2-amino-4-hydroxymethylthiazole-5-carboxylic acid methyl ester

The compound (4.68 g) obtained in Step 2 was suspended in dichloromethane (160 ml), and boron tribromide (1.0M dichloromethane solution, 35 ml) was added dropwise with stirring under ice-cooling. The reaction mixture was stirred under ice-cooling for 90 min, 4N aqueous sodium hydroxide solution (26 ml) was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration, washed with water and acetone, and dried to give the title compound (3.15 g).

¹H-NMR (CD₃OD, 400 MHz) δ: 3.78 (3H, s), 4.73 (2H, s).

Step 4 2-amino-4-formylthiazole-5-carboxylic acid methyl ester

To a solution of the compound (1.35 g) obtained in Step 3 in 1,4-dioxane (68 ml)/N,N-dimethylformamide (13 ml) was added manganese dioxide (3.68 g) at room temperature and the mixture was stirred at room temperature for 40 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.20 g).

¹H-NMR (DMSO-d₆, 400 MHz) δ: 3.81 (3H, s), 8.05 (2H, br s), 10.28 (1H, s).

Step 5 2-amino-6H-thiazolo[4,5-d]pyridazin-7-one

To a solution of the compound (1.20 g) obtained in Step 4 in ethanol (120 ml) was added hydrazine monohydrate (374 μl), and the mixture was heated under reflux for 24 hr. Since the reaction was not completed, acetic acid (1.0 ml) was added, and the mixture was further heated under reflux for 20 hr. The reaction mixture was concentrated under reduced pressure to an amount of 5 ml, a small amount of ethanol was added, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration, washed with a small amount of ethanol, and dried to give the title compound (822 mg).

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.08 (1H, s), 8.26 (2H, br s), 12.75 (1H, br s).

Step 6 2-chloro-6H-thiazolo[4,5-d]pyridazin-7-one

The compound (822 mg) obtained in Step 5 was suspended in 6N aqueous hydrochloric acid solution (6.6 ml), and sodium nitrite (1.69 g) was added in several portions at room temperature. After stirring the obtained suspension at room temperature for 30 min, the reaction mixture was diluted with water, and the solid was collected by filtration, washed with water and a small amount of acetone, and dried to give the title compound (770 mg).

¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.61 (1H, s), 13.41 (1H, br s).

Step 7 (R)-4-(7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixed solution of the compound (26 mg) obtained in Example 783, the compound (10 mg) obtained in Step 6 and isopropanol (1.0 ml) was added triethylamine (14 μl) at room temperature, and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:20, developed twice) to give the title compound (31 mg).

¹H-NMR (DMSO-d₆, 400 MHz) δ: 3.33-3.40 (1H, m), 3.60-3.85 (3H, m), 3.95-4.20 (3H, m), 4.39 (1H, d, J=13.0 Hz), 4.64 (1H, dd, J=4.8, 2.4 Hz), 7.23 (4H, dd, J=22.3, 8.6 Hz), 7.50 (2H, d, J=8.6 Hz), 7.93 (2H, dt, J=9.7, 2.5 Hz), 8.13 (1H, s), 8.81 (1H, t, J=5.9 Hz), 12.87 (1H, s).

Example 1019 Step 1 5-bromo-[1,3,4]thiadiazol-2-ylamine

To a suspension of [1,3,4]-thiadiazol-2-ylamine (11 g) and sodium acetate (36 g) in acetic acid (160 ml) was slowly added dropwise a solution of bromine (6.0 ml) in acetic acid (40 ml) at room temperature over 30 min. After dropwise addition, the mixture was further stirred for 3 hr, and water (200 ml) was added to the reaction mixture. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (17 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 7.51 (2H, br s).

Step 2 N-(5-bromo-[1,3,4]thiadiazol-2-yl)-3-oxo-butylamide

To a suspension of the compound (2.8 g) obtained in Step 1 in toluene (200 ml) was slowly added dropwise 4-methyleneoxetan-2-one (10 ml) at 100° C., and the mixture was stirred at the same temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the obtained crude product (3.5 g) containing the title compound as a main component was washed with water-containing methanol, and dried to give the title compound (2.0 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 2.21 (3H, s), 3.79 (2H, s), 12.95 (1H, s).

Step 3 2-bromo-5-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-one

To concentrated sulfuric acid (10 ml) heated to 60° C. was added the compound (1.3 g) obtained in Step 2 in divided portions, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was poured into ice (100 g), and the mixture was neutralized with an aqueous solution (100 ml) of sodium carbonate (20 g). The organic layer was extracted with chloroform (50 ml), and dried to give the title compound (810 mg).

¹H-NMR (CDCl₃, 300 MHz) δ: 2.52 (3H, s), 6.14 (1H, s).

Step 4 (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixed solution of the compound (0.038 g) obtained in Example 783, the compound (0.023 g) obtained in Step 3 and ethanol (1.0 ml) was added N,N-diisopropylethylamine (0.019 ml) at room temperature. After stirring at 100° C. for 3 hr, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:9) to give the title compound (0.032 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 2.36 (3H, s), 3.01 (1H, td, J=12.2, 3.1 Hz), 3.15 (1H, dd, J=13.2, 4.1 Hz), 3.57 (1H, ddd, J=13.8, 10.7, 2.4 Hz), 3.90 (2H, tt, J=16.4, 3.0 Hz), 4.28 (1H, d, J=13.2 Hz), 4.36 (1H, dd, J=13.6, 5.3 Hz), 4.43 (1H, dd, J=14.1, 5.5 Hz), 4.66 (1H, d, J=1.9 Hz), 6.05 (1H, d, J=0.8 Hz), 7.15 (2H, d, J=7.9 Hz), 7.26 (2H, d, J=8.7 Hz), 7.32 (2H, d, J=8.3 Hz), 7.57 (1H, t, J=5.7 Hz), 7.88 (2H, d, J=8.7 Hz).

Example 1030 Step 1 2-amino-5-(tert-butyldimethylsilyloxymethyl)-thiazole-4-carboxylic acid methyl ester

To a solution of methyl dichloroacetate (3.08 g) in diethyl ether (12 ml)-methanol (6 ml) was added (tert-butyldimethylsilyloxy)acetaldehyde (5.0 g) with stirring under ice-cooling. With stirring under ice-cooling, 28% sodium methoxide methanol solution (4.83 ml) was added dropwise, and the mixture was further stirred for 3 hr. With stirring under ice-cooling, water was added, and the temperature of the mixture was raised to room temperature. The mixture was partitioned by adding diethyl ether, and the organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. To a solution of the concentrated residue in acetonitrile (30 ml) was added thiourea (1.64 g) with stirring at room temperature. After stirring at bath temperature of 70° C. for 3 hr, the reaction mixture was returned to room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the concentrated residue, and the insoluble material was filtered off. The filtrate was partitioned by adding sodium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=3:7) to give the title compound (2.05 g).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 0.08 (6H, s), 0.89 (9H, s), 3.72 (3H, s), 4.99 (2H, s), 7.02 (2H, br s).

Step 2 2-amino-5-hydroxymethyl-thiazole-4-carboxylic acid methyl ester

To a solution of the compound (2.03 g) obtained in Step 1 in tetrahydrofuran (40 ml) was added dropwise, with stirring under ice-cooling, 1.0M tetrabutylammonium fluoride tetrahydrofuran solution (7.38 ml). After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to give the title compound (1.06 g).

¹H-NMR (CDCl₃, 300 MHz) δ: 3.42 (1H, t, J=7.0 Hz), 3.93 (3H, s), 4.87 (2H, d, J=7.0 Hz), 4.98 (2H, br s).

Step 3 2-amino-5-formyl-thiazole-4-carboxylic acid methyl ester

The compound (1.05 g) obtained in Step 2 was suspended in chloroform (50 ml), manganese dioxide (4.86 g) was added, with stirring at room temperature, and the mixture was stirred at the same temperature for 3 days. The reaction mixture was concentrated, tetrahydrofuran (150 ml) and activated carbon were added, and the mixture was heated under reflux. The insoluble material was filtered off when it was hot, and the insoluble material was washed with a heated mixed solvent (tetrahydrofuran:N,N-dimethylformamide:methanol=8:1:1). The filtrate was concentrated under reduced pressure, and the obtained crude crystals were suspended in diethyl ether, collected by filtration and dried to give the title compound (782 mg).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 3.85 (3H, s), 8.41 (2H, br s), 10.14 (1H, s).

Step 4 2-amino-5H-thiazolo[4,5-d]pyridazin-4-one

The compound (788 mg) obtained in Step 3 was suspended in ethanol (7.8 ml), and hydrazine monohydrate (243 μl) and acetic acid (780 μl) were added, with stirring at room temperature. The mixture was stirred overnight at a bath temperature of 100° C. and returned to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained crude crystals were suspended in methanol, collected by filtration and dried to give the title compound (690 mg).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 8.07 (2H, br s), 8.25 (1H, s), 12.67 (1H, br s).

Step 5 2-chloro-5H-thiazolo[4,5-d]pyridazin-4-one

The compound (688 mg) obtained in Step 4 was suspended in 6N aqueous hydrochloric acid solution (10 ml), and sodium nitrite (1.41 g) was added in several portions with stirring at room temperature, and the mixture was further stirred at room temperature for 1 hr. Water was added, with stirring at room temperature, and the solid was collected by filtration, washed with water, and dried to give the title compound (571 mg).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 8.61 (1H, s), 13.25 (1H, br s).

Step 6 (R)-4-(4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixture of the compound (87 mg) obtained in Example 983, Step 2 and the compound (32 mg) obtained in Step 5 in isopropanol (0.9 ml) was added N,N-diisopropylethylamine (30 μl) at room temperature. After stirring overnight at room temperature, and the mixture was stirred with heating under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=5:95) to give the title compound (84 mg).

¹H-NMR (CDCl₃, 300 MHz) δ: 3.07-3.17 (1H, m), 3.27 (1H, dd, J=13.4, 4.3 Hz), 3.44-3.54 (1H, m), 3.95 (1H, d, J=14.3 Hz), 4.28-4.39 (2H, m), 4.47 (1H, dd, J=15.3, 6.2 Hz), 4.56 (1H, d, J=12.8 Hz), 4.67 (1H, br s), 6.99 (1H, t, J=5.7 Hz), 7.13 (2H, d, J=7.9 Hz), 7.22 (2H, d, J=9.0 Hz), 7.81 (2H, d, J=8.3 Hz), 8.01 (2H, d, J=8.3 Hz), 8.04 (1H, s), 10.28 (1H, br s).

Step 7 (R)-4-(5-methyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a solution of the compound (40 mg) obtained in Step 6 in THF (0.8 ml) were added methanol (3.7 μl), triphenylphosphine (24 mg) and diisopropyl azodicarboxylate (18 μl) with stirring under ice-cooling, and the mixture was stirred overnight at room temperature. Methanol (1.2 μl), triphenylphosphine (8 mg) and diisopropyl azodicarboxylate (6 μl) was added at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=5:95) to give the title compound (29 mg).

¹H-NMR (CDCl₃, 300 MHz) δ: 3.08-3.17 (1H, m), 3.27 (1H, dd, J=13.4, 4.3 Hz), 3.45-3.55 (1H, m), 3.85 (3H, s), 3.93 (1H, d, J=14.3 Hz), 4.25-4.37 (2H, m), 4.46 (1H, dd, J=15.1, 6.4 Hz), 4.56 (1H, d, J=13.6 Hz), 4.68 (1H, br s), 7.05-7.13 (3H, m), 7.20 (2H, d, J=8.7 Hz), 7.80 (2H, d, J=8.7 Hz), 7.98-8.02 (3H, m).

Example 1100 Step 1 (R)-4-(4-bromo-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester

(R)-4-tert-butoxycarbonyl-piperazine-2-carboxylic acid (500 mg) was suspended in a mixed solvent of 1,4-dioxane (5.0 ml) and water (2.5 ml), 2N aqueous sodium hydroxide solution (1.1 ml) and triethylamine (440 mg) were successively added with stirring under ice-cooling, and a solution of 4-bromobenzenesulfonyl chloride (610 mg) in 1,4-dioxane (1.0 ml) was added dropwise. After stirring overnight at room temperature, 10% aqueous citric acid solution and ethyl acetate were added with stirring under ice-cooling. The reaction mixture was partitioned, and the organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give a crude product (548 mg) containing the title compound as a main component. A part thereof was directly used for the next reaction.

Step 2 (R)-4-(4-cyclopropyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester

Under an argon atmosphere, to a suspension of palladium diacetate (15 mg) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (61 mg) in toluene (5.8 ml) were successively added the compound (290 mg) obtained in Step 1, cyclopropylboronic acid (83 mg) and tripotassium phosphate (1.21 g). The mixture was stirred at 100° C. for 1 hr. Ethyl acetate was added at room temperature and the reaction mixture was adjusted to pH 4 by adding 1N aqueous hydrochloric acid solution with stirring under ice-cooling. The obtained suspension was filtered through celite and partitioned. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (328 mg) containing the title compound as a main component.

¹H-NMR (CDCl₃, 300 MHz) δ: 0.72-0.81 (2H, m), 1.02-1.13 (2H, m), 1.29-1.45 (9H, m), 1.88-2.01 (1H, m), 2.75-2.96 (1H, m), 3.01-3.16 (1H, m), 3.29-3.46 (1H, m), 3.58-3.69 (1H, m), 3.93-4.12 (1H, m), 4.46-4.67 (2H, m), 7.13 (2H, d, J=8.3 Hz), 7.64 (2H, d, J=8.3 Hz).

Step 3 (R)-4-(4-cyclopropyl-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of the compound (168 mg) obtained in Step 2 in N,N-dimethylformamide (1.7 ml) were successively added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg), 1-hydroxybenzotriazole hydrate (75 mg) and 4-trifluoromethoxybenzylamine (85 mg). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (132 mg).

¹H-NMR (CDCl₃, 400 MHz) δ: 0.78-0.84 (2H, m), 1.10-1.17 (2H, m), 1.93-2.01 (1H, m), 2.62-2.82 (2H, br m), 3.24-3.35 (1H, m), 3.60-3.83 (2H, br m), 4.37-4.64 (4H, m), 6.94-7.01 (1H, m), 7.16-7.21 (4H, m), 7.25-7.30 (2H, m), 7.71 (2H, d, J=8.6 Hz).

Step 4 (R)-1-(4-cyclopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

4N Hydrogen chloride/1,4-dioxane solution (1.3 ml) was added to the compound (130 mg) obtained in Step 3, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (chloroform:methanol=9:1) to give the title compound (88 mg).

¹H-NMR (CDCl₃, 300 MHz) δ: 0.74-0.83 (2H, m), 1.08-1.17 (2H, m), 1.90-2.01 (1H, m), 2.38-2.50 (2H, m)', 2.76 (1H, d, J=12.8 Hz), 3.04-3.17 (1H, m), 3.54 (1H, d, J=12.8 Hz), 3.71-3.80 (1H, m), 4.31 (1H, d, J=3.8 Hz), 4.40-4.55 (2H, m), 7.11-7.21 (5H, m), 7.28 (2H, t, J=5.8 Hz), 7.69-7.72 (2H, m).

Step 5 (R)-4-(7-chloro-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-cyclopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixed solution of the compound (27 mg) obtained in Example 1001, Step 8, the compound (43 mg) obtained in Step 4 and chloroform (0.50 ml) was added N,N-diisopropylethylamine (19 μl) under ice-cooling. After stirring overnight at room temperature, the reaction mixture was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (66 mg).

Step 6 (R)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-cyclopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixed solution of the compound (66 mg) obtained in Step 5, ammonium formate (28 mg) and ethanol (1.3 ml) was added 10% palladium carbon (33 mg) with heating under reflux. The mixture was stirred at the same temperature for 10 min and ammonium formate (28 mg) and 10% palladium carbon (33 mg) were added and the mixture was stirred for 10 min. Ammonium formate (28 mg) and 10% palladium carbon (33 mg) were further added. The reaction mixture was allowed to return to room temperature, and diluted with ethanol. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), and the obtained crude product was suspended in hexane, collected by filtration, and dried to give the title compound (31 mg).

1H-NMR (CDCl₃, 300 MHz) δ: 0.74-0.82 (2H, m), 1.07-1.18 (2H, m), 1.89-1.99 (1H, m), 3.07-3.30 (2H, m), 3.33-3.48 (1H, m), 3.98 (1H, d, J=13.9 Hz), 4.30-4.54 (4H, m), 4.65 (1H, br s), 7.02 (1H, t, J=5.8 Hz), 7.13 (2H, d, J=8.3 Hz), 7.18-7.24 (4H, m), 7.74 (2H, d, J=8.7 Hz), 8.85 (1H, s).

Example 1099 Step 1 (R)-4-(7-chloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-cyclopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixture of (R)-1-(4-cyclopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide (39 mg) obtained in Example 1100, Step 4 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (20 mg) in chloroform (1.0 ml) was added N,N-diisopropylethylamine (20 μl) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, and the mixture was partitioned by adding water. The organic layer was dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (54 mg).

Step 2 (R)-1-(4-cyclopropyl-benzenesulfonyl)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide

To a mixture of the compound (54 mg) obtained in Step 1 and ammonium formate (49 mg) in ethanol (2.0 ml) was added 10% palladium carbon (50 mg) at 80° C. After stirring at 80° C. for 30 min, ammonium formate (49 mg) and 10% palladium carbon (50 mg) were added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (ethyl acetate) to give the title compound (24 mg).

¹H-NMR (CDCl₃, 400 MHz) δ: 0.76-0.80 (2H, m), 1.02-1.07 (2H, m), 1.10-1.16 (2H, m), 1.17-1.22 (2H, m), 1.89-1.97 (1H, m), 2.21-2.29 (1H, m), 3.06-3.14 (1H, m), 3.17-3.25 (1H, m), 3.37-3.45 (1H, m), 3.93 (1H, d, J=14.1 Hz), 4.27-4.51 (4H, m), 4.62 (1H, br s), 7.05 (1H, br s), 7.12 (2H, d, J=8.1 Hz), 7.19 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.6 Hz), 8.61 (1H, s).

The compounds obtained in the above-mentioned Examples and the compounds synthesized by a method similar thereto and other conventional methods where necessary are shown in Table 1-Table 226.

The NMR data and mass spectrum data of the compounds of the present invention are shown in Table 227-Table 459.

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Lengthy table referenced here US20120107273A1-20120503-T00219 Please refer to the end of the specification for access instructions.

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Lengthy table referenced here US20120107273A1-20120503-T00230 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00231 Please refer to the end of the specification for access instructions.

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Lengthy table referenced here US20120107273A1-20120503-T00240 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00241 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00242 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00243 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00244 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00245 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00246 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00247 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00248 Please refer to the end of the specification for access instructions.

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Lengthy table referenced here US20120107273A1-20120503-T00342 Please refer to the end of the specification for access instructions.

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Lengthy table referenced here US20120107273A1-20120503-T00344 Please refer to the end of the specification for access instructions.

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Lengthy table referenced here US20120107273A1-20120503-T00346 Please refer to the end of the specification for access instructions.

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Lengthy table referenced here US20120107273A1-20120503-T00389 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00390 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00391 Please refer to the end of the specification for access instructions.

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Lengthy table referenced here US20120107273A1-20120503-T00393 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00394 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00395 Please refer to the end of the specification for access instructions.

Lengthy table referenced here US20120107273A1-20120503-T00396 Please refer to the end of the specification for access instructions.

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Lengthy table referenced here US20120107273A1-20120503-T00459 Please refer to the end of the specification for access instructions.

The evaluation of the HCV polymerase inhibitory activity of the compound of the present invention is explained in the following. This polymerase is an enzyme coded for by the non-structural protein region called NS5B on the genome RNA of HCV.

Experimental Example [I] Assay of Enzyme Inhibitory Activity i) Preparation of Enzyme (HCV Polymerase)

Using, as a template, a cDNA clone corresponding to the full length genome RNA of HCV BK strain (type 1b) obtained from the blood of a patient with hepatitis C, a region encoding NS5B (J Virol 1991 March, 65(3), 1105-13, 544 amino acids after deletion of 47 amino acids on the C-terminal) was amplified by PCR. The objective gene was prepared by adding a 6 His tag {base pair encoding 6 continuous histidine (H is)} to the 3′ end thereof and transformed to Escherichia coli. The Escherichia coli capable of producing the objective protein was cultured. The obtained cells were suspended in a buffer solution and crushed in a microfluidizer. The supernatant was obtained by centrifugation and applied to various column chromatographys {mono-S, Sephacryl S-200 (Pharmacia)}, inclusive of metal chelate chromatography, to give a standard enzyme product.

Standard enzyme products for type la (cloned from the blood of patients) were also obtained by a similar method.

The amino acids sequence (from N-terminal to 544 amino acids+GS+6H is tag) is shown below.

(SEQ ID NO: 1) SMSYSWTGALITPCAAEEQKLPINALSNSLLRHHNLVYSTTSRSACQRQKKVTFDRLQVLDSHY QDVLKE VKAAASKVKANLLSVEEACSLTPPHSARSKFGYGAKDVRCHARKAVNHINSVWKDLLEDSVTPI DTTIMA KNEVFCVQPEKGGRKPARLIVFPDLGVRVCEKMALYDVVSKLPLAVMGSSYGFQYSPGQRVEFL VQAWKS KRTPMGFSYDTRCFDSTVTESDIRTEEAIYQCCDLDPQARVAIKSLTERLYVGGPLTNSRGENC GYRRCR ASGVLTTSCGNTLTCYIKAQAACRAAGLQDCTMLVCGDDLVVICESAGVQEDAASLRAFTEAMT RYSAPP GDPPQPEYDLELITSCSSNVSVAHDGAGKRVYYLTRDPTTPLARAAWETARHTPVNSWLGNIIM FAPTLW VRMILLTHFFSVLIARDQLEQALDCEIYGACYSIEPLDLPPIIQRLHGLSAFSLHSYSPGEINR VAACLR KLGVPPLRAWRHRARSVRAKLLSRGGRAAICGKYLFNWAVKTKLKLTPIAAAGQGSHHHHHH

ii) Synthesis of Substrate RNA

Using a synthetic primer designed based on the sequence of HCV genomic 3′ untranslated region, a DNA fragment (148 bp) containing polyU and 3′X sequence was entirely synthesized and cloned into plasmid pBluescript SK II(+) (Stratagene). The cDNA encoding full length NS5B, which was prepared in i) above, was digested with restriction enzyme KpnI to give a cDNA fragment containing the nucleotide sequence of from the restriction enzyme cleavage site to the termination codon. This cDNA fragment was inserted into the upstream of 3′ untranslated region of the DNA in pBluescript SK II(+) and ligated. The about 450 bp inserted DNA sequence was used as a template in the preparation of substrate RNA. This plasmid was cleaved immediately after the 3′X sequence, linearized and purified by phenol-chloroform treatment and ethanol precipitation to give DNA.

RNA was synthesized (37° C., 4 hr) by run-off method using this purified DNA as a template, a promoter of pBluescript SK II(+), MEGAscript RNA synthesis kit (Ambion) and T7 RNA polymerase. DNase I was added and the mixture was incubated for 1 hr. The template DNA was removed by decomposition to give a crude RNA product. This crude product was treated with phenol-chloroform and purified by ethanol precipitation to give the objective substrate RNA.

This RNA was applied to urea denaturation polyacrylamide gel electrophoresis to confirm the quality thereof and preserved at −80° C.

iii) Assay of Enzyme (HCV Polymerase) Inhibitory Activity

A test substance (compound of the present invention) and a reaction mixture (30 μl) having the following composition were reacted at 25° C. for 60 min.

10% Trichloroacetic acid and 1% sodium pyrophosphate solution (150 μl) at 4° C. was added to this reaction mixture to stop the reaction. The reaction mixture was left standing at 4° C. for 15 min to insolubilize RNA. This RNA was trapped on a glass filter (PerkinElmer, GF/B) upon filtration by suction. This filter was washed with a solution containing 1% trichloroacetic acid and 0.1% sodium pyrophosphate, washed with 90% ethanol and dried. A liquid scintillation cocktail (PerkinElmer) was added and the radioactivity of RNA synthesized by the enzyme reaction was measured on a liquid scintillation counter.

The HCV polymerase inhibitory activity (IC₅₀) of the compound of the present invention was calculated from the values of radioactivity of the enzyme reaction with and without the test substance.

The results are shown in Tables 460-497. IC₅₀ shows the following ranges.

A: not less than 1 μM B: not less than 0.1 μM and less than 1 μM C: less than 0.1 μM

A preferable compound of the present invention is a compound having an HCV polymerase inhibitory activity (IC₅₀) of less than 0.1 μM.

In addition, a compound showing high inhibitory activity for both type 1a and type 1b is preferable, and a compound showing a high inhibitory activity of less than 0.1 μM for both type 1a and type 1b enzymes is one of the most preferable embodiments.

Reaction mixture: HCV polymerase (type 1b 0.5 μg/ml or type la 1.5 μg/m) obtained in i), substrate RNA (5 μg/ml) obtained in ii), ATP (50 μM), GTP (50 μM), CTP (50 μM), UTP (2 μM), [5,6-³H]UTP (30-60 Ci/mmol (Amersham Biosciences), 1 μCi) 20 mM Tris-HCl (pH 7.5), EDTA (1 mM), MgCl₂ (5 mM), NaCl (50 mM), DTT (1 mM), BSA (0.01%)

TABLE 460 Example No. 1a 1b 1 A A 2 B B 3 C C 4 B B 5 A A 6 C C 7 C C 8 C C 9 C C 10 C C 11 C C 12 C C 13 C C 14 C C 15 A A 16 A A 17 A A 18 B B 19 A A 20 A A 21 A A 22 A A 23 A A 24 A A 25 A A 26 A A 27 A A 28 A A 29 A A 30 A A

TABLE 461 Example No. 1a 1b 31 A A 32 A A 33 A A 34 A A 35 A A 36 B A 37 B B 38 A A 39 A A 40 A A 41 A A 42 A A 43 A A 44 A A 45 A A 46 A A 47 A A 48 A A 49 A A 50 A A 51 A A 52 A A 53 B B 54 A A 55 A A 56 A A 57 A A 58 A A 59 A A 60 A A

TABLE 462 Example No. 1a 1b 61 A A 62 A A 63 A A 64 A A 65 A A 66 A A 67 A A 68 B B 69 A A 70 A A 71 A A 72 A B 73 A A 74 A A 75 A A 76 A A 77 A A 78 A A 79 A A 80 A A 81 A A 82 A A 83 A A 84 A A 85 B A 86 A A 87 A A 88 A A 89 A A 90 A A

TABLE 463 Example No. 1a 1b 91 A A 92 A A 93 A A 94 A A 95 A A 96 A A 97 A A 98 A A 99 A A 100 A A 101 A A 102 A A 103 A A 104 A A 105 A A 106 A A 107 A A 108 A A 109 A A 110 A A 111 A A 112 A A 113 A A 114 A A 115 A A 116 A A 117 B B 118 A A 119 A A 120 A A

TABLE 464 Example No. 1a 1b 121 A A 122 A A 123 A A 124 A A 125 A A 126 A A 127 A A 128 A A 129 A A 130 A A 131 A B 132 A A 133 A A 134 A A 135 A A 136 A A 137 C C 138 A A 139 B B 140 A A 141 A A 142 A A 143 A A 144 B B 145 A A 146 A B 147 A B 148 A A 149 A A 150 A A

TABLE 465 Example No. 1a 1b 151 A A 152 A A 153 A A 154 B B 155 A A 156 A A 157 A A 158 A A 159 A A 160 B B 161 A A 162 A A 163 B B 164 A A 165 A A 166 A A 167 A A 168 A A 169 A A 170 A A 171 A A 172 A B 173 B B 174 B B 175 B B 176 B B 177 B B 178 B B 179 B B 180 A B

TABLE 466 Example No. 1a 1b 181 A A 182 B B 183 B B 184 B B 185 A B 186 A B 187 A A 188 B B 189 A A 190 A B 191 B B 192 B B 193 B B 194 C C 195 B B 196 A A 197 A A 198 A A 199 A B 200 A B 201 A A 202 A B 203 B C 204 B B 205 C C 206 B B 207 C C 208 C C 209 A A 210 A A

TABLE 467 Example No. 1a 1b 211 B B 212 B C 213 B B 214 B B 215 B C 216 B B 217 A A 218 B B 219 C C 220 C C 221 A A 222 B B 223 B B 224 A A 225 B B 226 A A 227 B B 228 B B 229 C C 230 C C 231 A A 232 B B 233 A A 234 A A 235 A A 236 B B 237 C C 238 A B 239 A B 240 B C

TABLE 468 Example No. 1a 1b 241 B B 242 B B 243 A A 244 B B 245 A B 246 A B 247 B C 248 A B 249 A A 250 B B 251 A A 252 B B 253 C C 254 B C 255 C C 256 B B 257 C C 258 C C 259 B C 260 B B 261 A B 262 A A 263 B B 264 C C 265 A A 266 B B 267 A B 268 A B 269 A A 270 A B

TABLE 469 Example No. 1a 1b 271 A A 272 A B 273 A B 274 A B 275 B B 276 B B 277 A B 278 C C 279 B B 280 B B 281 B C 282 B C 283 A A 284 B C 285 B C 286 B B 287 C C 288 B B 289 A A 290 A B 291 C C 292 B C 293 B B 294 C C 295 C C 296 C C 297 C C 298 B B 299 C C 300 C C

TABLE 470 Example No. 1a 1b 301 C C 302 B C 303 C C 304 B B 305 B C 306 B B 307 B C 308 A A 309 C C 310 B C 311 B B 312 A B 313 C C 314 B B 315 B C 316 B B 317 B B 318 C C 319 A B 320 A A 321 C C 322 C C 323 C C 324 C B 325 A B 326 B B 327 C C 328 C C 329 C C 330 A B

TABLE 471 Example No. 1a 1b 331 C C 332 B C 333 C C 334 A A 335 C C 336 A A 337 A B 338 A B 339 C C 340 C C 341 C C 342 A B 343 C C 344 C C 345 A B 346 A A 347 B B 348 B B 349 A B 350 A A 351 A A 352 A B 353 B B 354 C C 355 C C 356 C C 357 A B 358 C C 359 C C 360 C C

TABLE 472 Example No. 1a 1b 361 C C 362 A B 363 C C 364 C C 365 C C 366 C C 367 C C 368 A B 369 C C 370 B C 371 B B 372 B C 373 A B 374 C C 375 C C 376 C C 377 C C 378 C C 379 C C 380 C C 381 C C 382 B B 383 C C 384 B B 385 C C 386 C C 387 C C 388 B C 389 B C 390 B C

TABLE 473 Example No. 1a 1b 391 B B 392 A A 393 A A 394 C C 395 A A 396 A A 397 A A 398 B C 399 C C 400 C C 401 A B 402 A A 403 A A 404 A A 405 A A 406 C C 407 B C 408 C C 409 B B 410 C B 411 C C 412 C B 413 B C 414 C C 415 C C 416 B C 417 C C 418 A A 419 B B 420 A A

TABLE 474 Example No. 1a 1b 421 A A 422 A A 423 C C 424 C C 425 C C 426 A B 427 A A 428 C C 429 C C 430 B B 431 B B 432 C C 433 A A 434 C C 435 C C 436 C C 437 C C 438 C C 439 A B 440 C C 441 C C 442 B C 443 B C 444 B B 445 B C 446 B C 447 B C 448 C C 449 C C 450 C C

TABLE 475 Example No. 1a 1b 451 C C 452 C C 453 C C 454 C C 455 C C 456 C C 457 C C 458 C C 459 C C 460 C C 461 C C 462 C C 463 A A 464 C C 465 C C 466 C C 467 C B 468 C C 469 B B 470 B B 471 B C 472 C C 473 C C 474 C C 475 B C 476 B B 477 A A 478 C C 479 C C 480 C C

TABLE 476 Example No. 1a 1b 481 B B 482 B C 483 A A 484 B C 485 C C 486 C C 487 C C 488 B C 489 A A 490 C B 491 C C 492 A B 493 B B 494 C C 495 A B 496 A A 497 A A 498 B B 499 C C 500 C C 501 C C 502 B B 503 B C 504 C C 505 C C 506 C C 507 C C 508 C C 509 C C 510 C C

TABLE 477 Example No. 1a 1b 511 C C 512 C C 513 C C 514 C C 515 C C 516 C C 517 C C 518 C C 519 B B 520 A B 521 A B 522 C C 523 B B 524 C C 525 C C 526 B B 527 B B 528 B C 529 C C 530 B C 531 C C 532 C C 533 A A 534 C C 535 C C 536 B C 537 C C 538 C C 539 B B 540 A A

TABLE 478 Example No. 1a 1b 541 B B 542 C C 543 C C 544 C C 545 C C 546 C C 547 C C 548 C C 549 C C 550 B B 551 B B 552 A B 553 C C 554 B C 555 B B 556 C C 557 C C 558 B C 559 C C 560 C C 561 C C 562 C C 563 C C 564 C C 565 B C 566 B C 567 B C 568 A A 569 B C 570 C C

TABLE 479 Example No. 1a 1b 571 C C 572 C C 573 C C 574 C C 575 C C 576 C C 577 C C 578 C C 579 C C 580 C C 581 C C 582 B B 583 C C 584 C C 585 B B 586 C C 587 B C 588 C C 589 C C 590 C C 591 C C 592 C C 593 C C 594 C C 595 C C 596 C C 597 C C 598 B B 599 B A 600 C C

TABLE 480 Example No. 1a 1b 601 C C 602 C C 603 B B 604 B C 605 C C 606 C C 607 B B 608 B B 609 A B 610 B B 611 A A 612 A B 613 A A 614 B B 615 C C 616 C C 617 C C 618 C C 619 C C 620 C C 621 A A 622 C B 623 C B 624 A B 625 C C 626 C C 627 C C 628 B C 629 B C 630 C C

TABLE 481 Example No. 1a 1b 631 C C 632 C C 633 C C 634 B A 635 A B 636 A A 637 A A 638 C C 639 A B 640 C C 641 B B 642 A A 643 A A 644 A A 645 A A 646 A A 647 A B 648 C C 649 A A 650 B C 651 C C 652 C C 653 C C 654 A A 655 B B 656 C C 657 C C 658 C C 659 C C 660 C C

TABLE 482 Example No. 1a 1b 661 C C 662 A B 663 C C 664 C C 665 A A 666 A A 667 A B 668 A A 669 A A 670 A A 671 A A 672 A A 673 A A 674 A A 675 A A 676 C C 677 A A 678 A A 679 A A 680 A B 681 A A 682 A A 683 C C 684 B B 685 B B 686 C C 687 C C 688 B B 689 C C 690 C C

TABLE 483 Example No. 1a 1b 691 C C 692 C C 693 A B 694 C C 695 C C 696 C C 697 C C 698 C C 699 C C 700 C C 701 C C 702 A A 703 A A 704 C C 705 A A 706 A A 707 C C 708 C C 709 C C 710 B B 711 B C 712 C C 713 C C 714 C C 715 C C 716 A A 717 A A 718 A B 719 A A 720 C C

TABLE 484 Example No. 1a 1b 721 A A 722 B C 723 B C 724 C C 725 C C 726 C C 727 C C 728 B B 729 C C 730 C C 731 C C 732 C C 733 B B 734 B B 735 C C 736 C C 737 C C 738 C C 739 C C 740 C C 741 B C 742 B C 743 C C 744 C C 745 C C 746 C C 747 C C 748 C C 749 C C 750 C C

TABLE 485 Example No. 1a 1b 751 C C 752 C C 753 C C 754 C C 755 C C 756 C C 757 C C 758 C C 759 C C 760 C C 761 C C 762 C C 763 C C 764 C C 765 C C 766 B C 767 C C 768 C C 769 C C 770 C C 771 C C 772 C C 773 C C 774 C C 775 C C 776 C C 777 C C 778 C C 779 C C 780 B C

TABLE 486 Example No. 1a 1b 781 C C 782 C C 783 A A 784 C C 785 C C 786 C C 787 C C 788 C C 789 C C 790 C C 791 C C 792 C C 793 C C 794 C C 795 C C 796 C C 797 C C 798 B C 799 C C 800 C C 801 C C 802 C C 803 C C 804 A A 805 C C 806 C C 807 C C 808 C C 809 C C 810 C C

TABLE 487 Example No. 1a 1b 811 B B 812 C C 813 C C 814 C C 815 C C 816 C C 817 C C 818 C C 819 C C 820 C C 821 C C 822 C C 823 B B 824 C C 825 C C 826 C C 827 C C 828 C C 829 B C 830 B C 831 A A 832 C C 833 A A 834 B B 835 C C 836 C C 837 A A 838 A A 839 C C 840 C C

TABLE 488 Example No. 1a 1b 841 C C 842 C C 843 C C 844 C C 845 C C 846 B C 847 C C 848 C C 849 B C 850 C C 851 C C 852 C C 853 A B 854 C C 855 C C 856 B C 857 C C 858 C C 859 B C 860 C C 861 C C 862 C C 863 C C 864 B C 865 C C 866 C C 867 B B 868 C C 869 C C 870 C C

TABLE 489 Example No. 1a 1b 871 C C 872 C C 873 C C 874 C C 875 C C 876 C C 877 C C 878 C C 879 C C 880 C C 881 C C 882 B C 883 C C 884 C C 885 C C 886 C C 887 C C 888 C C 889 A A 890 C C 891 C C 892 C C 893 C C 894 C C 895 C C 896 C C 897 C C 898 C C 899 A B 900 C C

TABLE 490 Example No. 1a 1b 901 C C 902 C C 903 C C 904 B C 905 C C 906 C C 907 C C 908 C C 909 B C 910 C C 911 C C 912 C C 913 C C 914 C C 915 C C 916 C C 917 C C 918 C C 919 C C 920 B C 921 B C 922 C C 923 B B 924 B B 925 C C 926 C C 927 C C 928 C C 929 C C 930 C C

TABLE 491 Example No 1a 1b 931 C C 932 C C 933 C C 934 C C 935 C C 936 A A 937 C C 938 B C 939 C C 940 C C 941 C C 942 C C 943 C C 944 C C 945 C C 946 C C 947 C C 948 C C 949 C C 950 C C 951 C C 952 C C 953 C C 954 C C 955 C C 956 C C 957 C C 958 C C 959 C C 960 C C

TABLE 492 Example No. 1a 1b 961 C C 962 C C 963 C C 964 C C 965 C C 966 C C 967 C C 968 C C 969 C C 970 C C 971 C C 972 C C 973 C C 974 A A 975 C C 976 C C 977 C C 978 C C 979 C C 980 C C 981 C C 982 C C 983 C C 984 C C 985 C C 986 C C 987 C C 988 A A 989 C C 990 C C

TABLE 493 Example No. 1a 1b 991 C C 992 C C 993 A A 994 C C 995 C C 996 C C 997 C C 998 C C 999 C C 1000 C C 1001 C C 1002 C C 1003 C C 1004 C C 1005 C C 1006 C C 1007 C C 1008 C C 1009 C C 1010 C C 1011 C C 1012 C C 1013 C C 1014 C C 1015 C C 1016 C C 1017 C C 1018 C C 1019 C C 1020 C C

TABLE 494 Example No. 1a 1b 1021 C C 1022 B B 1023 C C 1024 C C 1025 C C 1026 C C 1027 C C 1028 C C 1029 B C 1030 C C 1031 B B 1032 C C 1033 C C 1034 C C 1035 C C 1036 C C 1037 C C 1038 B B 1039 C C 1040 C C 1041 C C 1042 C C 1043 C C 1044 C C 1045 C C 1046 C C 1047 C C 1048 C C 1049 C C 1050 B B

TABLE 495 Example No. 1a 1b 1051 C C 1052 C C 1053 C C 1054 C C 1055 C C 1056 C C 1057 C C 1058 C C 1059 C C 1060 C C 1061 C C 1062 C C 1063 C C 1064 C C 1065 C C 1066 C C 1067 C C 1068 C C 1069 C C 1070 C C 1071 C C 1072 C C 1073 C C 1074 C C 1075 C C 1076 C C 1077 C C 1078 C C 1079 C C 1080 C C

TABLE 496 Example No. 1a 1b 1081 C C 1082 C C 1083 C C 1084 C C 1085 C C 1086 C C 1087 C C 1088 C C 1089 C C 1090 C C 1091 C C 1092 B C 1093 C C 1094 B B 1095 B B 1096 C C 1097 B B 1098 C C 1099 C C 1100 C C 1101 C C 1102 C C 1103 B B 1104 C C 1105 B C 1106 C C 1107 B C 1108 B C 1109 C C 1110 C C

TABLE 497 Example No. 1a 1b 1111 C C 1112 C C 1113 C C 1114 C C 1115 B A 1116 B B 1117 A A 1121 C C 1122 C C 1123 C C

Formulation Example is given in the following. This example is merely for the purpose of exemplification and does not limit the invention.

Formulation Example

(a) compound of Example 1 10 g (b) lactose 50 g (c) corn starch 15 g (d) sodium carboxymethylcellulose 44 g (e) magnesium stearate  1 g

The entire amounts of (a), (b) and (c) and 30 g of (d) are kneaded with water, dried in vacuo and granulated. The obtained granules are mixed with 14 g of (d) and 1 g of (e) and processed into tablets with a tableting machine to give 1000 tablets each containing 10 mg of (a).

INDUSTRIAL APPLICABILITY

As is evident from the above-mentioned results, the compound of the present invention shows a high inhibitory activity against HCV polymerase.

Therefore, the compound of the present invention can provide a pharmaceutical agent effective for the prophylaxis or treatment of hepatitis C, based on the anti-HCV effect afforded by the HCV polymerase inhibitory activity. When used concurrently with a different anti-HCV agent, such as interferon, and/or an anti-inflammatory agent and the like, it can provide a pharmaceutical agent more effective for the prophylaxis or treatment of hepatitis C. Its high inhibitory activity specific to HCV polymerase suggests the possibility of the compound being a pharmaceutical agent with slight side effects, which can be used safely for humans.

Sequence Listing Free Text

SEQ ID NO: 1: artificial HCV polymerase derived from HCV BK strain (type 1a)

This application is based on a patent application No. 2006-115008 filed in Japan, the contents of which are hereby incorporated by reference.

LENGTHY TABLES The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20120107273A1). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3). 

1.-14. (canceled)
 15. A compound represented by the following formula [I-A] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring A is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following up A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and q1 is an integer of 1 to 4, group A: halogen atom, nitro group, cyano group, —OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅ (wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₂₋₁₀ alkynyl group optionally substituted b 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, group B: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkoxy group, amino group, C₁₋₄ alkylamino group, di(C₁₋₄ alkyl)amino group, carboxyl group, C₁₋₄ alkoxy-carbonyl group, carbamoyl group, C₁₋₄ alkylamino-carbonyl group, di(C₁₋₄ alkyl)amino-carbonyl group, heterocyclyl-carbonyl group, and tri(C₁₋₄ alkyl)ammoniumyl group (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group C: halogen atom, cyano group, hydroxyl group, carboxyl group, C₁₋₄ alkyl group, halogeno C₁₋₄ alkyl group, hydroxy C₁₋₄ alkyl group, carboxy C₁₋₄ alkyl group, C₁₋₄ alkoxy C₁₋₄ alkyl group, C₁₋₄ alkoxy group, and carboxy C₁₋₄ alkoxy group.
 16. A compound represented by the following formula [I-B] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring A is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group A: halogen atom, nitro group, cyano group, —OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅ (wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, group B: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkoxy group, amino group, C₁₋₄ alkylamino group, di(C₁₋₄ alkyl)amino group, carboxyl group, C₁₋₄ alkoxy-carbonyl group, carbamoyl group, C₁₋₄ alkylamino-carbonyl group, di(C₁₋₄ alkyl)amino-carbonyl group, heterocyclyl-carbonyl group, and tri(C₁₋₄ alkyl)ammoniumyl group (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group C: halogen atom, cyano group, hydroxyl group, carboxyl group, C₁₋₄ alkyl group, halogen C₁₋₄ alkyl group, hydroxy C₁₋₄ alkyl group, carboxy C₁₋₄ alkyl group, C₁₋₄ alkoxy C₁₋₄ alkyl group, C₁₋₄ alkoxy group, and carboxy C₁₋₄ alkoxy group.
 17. A compound represented by the following formula [I-C] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring A is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group A: halogen atom, nitro group, cyano group, —OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅ (wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, group B: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkoxy group, amino group, C₁₋₄ alkylamino group, di(C₁₋₄ alkyl)amino group, carboxyl group, C₁₋₄ alkoxy-carbonyl group, carbamoyl group, C₁₋₄ alkylamino-carbonyl group, di(C₁₋₄ alkyl)amino-carbonyl group, heterocyclyl-carbonyl group, and tri(C₁₋₄ alkyl)ammoniumyl group (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group C: halogen atom, cyano group, hydroxyl group, carboxyl group, C₁₋₄ alkyl group, halogeno C₁₋₄ alkyl group, hydroxy C₁₋₄ alkyl group, carboxy C₁₋₄ alkyl group, C₁₋₄ alkoxy C₁₋₄ alkyl group, C₁₋₄ alkoxy group, and carboxy C₁₋₄ alkoxy group.
 18. A compound represented by the following formula [I-D1] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring A is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), ring B1 is a phenyl group optionally substituted by 1 to 5 substituents selected from group A), and ring C2 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A′ (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group A′: halogen atom, nitro group, cyano group, —OR^(a1), —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅ (wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from group C, a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from group C, group A: halogen atom, nitro group, cyano group, —OR^(a1), —SR^(a2), NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅ (wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the follow group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, group B: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkoxy group, amino group, C₁₋₄ alkylamino group, di(C₁₋₄ alkyl)amino group, carboxyl group, C₁₋₄ alkoxy-carbonyl group, carbamoyl group, C₁₋₄ alkylamino-carbonyl group, di(C₁₋₄ alkyl)amino-carbonyl group, heterocyclyl-carbonyl group, and tri(C₁₋₄ alkyl)ammoniumyl group (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group C: halogen atom, cyano group, hydroxyl group, carboxyl group, C₁₋₄ alkyl group, halogeno C₁₋₄ alkyl group, hydroxy C₁₋₄ alkyl group, carboxy C₁₋₄ alkyl group, C₁₋₄ alkoxy C₁₋₄ alkyl group, C₁₋₄ alkoxy group, and carboxy C₁₋₄ alkoxy group.
 19. The compound of any one of claims 15 to 18, wherein ring A is a phenyl group optionally substituted by 1 to 5 substituents selected from group A, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 20. The compound of any one of claims 15 to 18, wherein n is 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 21. The compound of any one of claims 15 to 17, wherein the ring B is a phenyl group optionally substituted by 1 to 5 substituents selected from group A, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 22. The compound of any one of claims 15 to 17, wherein the ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A, and the heterocyclic group is selected from the group consisting of piperidinyl group, morpholinyl group, pyrrolidinyl group, piperazinyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, oxadiazolyl group, pyridyl group and pyrimidinyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 23. The compound of claim 16, wherein the ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A, and the heterocyclic group is selected from the group consisting of thiazolyl group, isothiazolyl group, isoxazolyl group, thiadiazolyl group, oxadiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group and pyrimidinyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 24. The compound of claim 17, wherein the ring C1 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A, and the heterocyclic group is selected from the group consisting of piperidinyl group, morpholinyl group, pyrrolidinyl group, piperazinyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, isoxazolyl group, pyridyl group and pyrimidinyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 25. The compound of claim 18, wherein the ring C2 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A′, and the heterocyclic group is selected from the group consisting of imidazolinyl group, thiazolinyl group, oxazolinyl group, thienyl group, dioxopyrrolidinyl group, dioxopyrrolinyl group, oxopyrrolidinyl group, oxothiadiazolinyl group, tetrahydrobenzothiazolyl group, thiazolyl group, thiadiazolyl group, pyrazolyl group, imidazolyl group, triazolyl group, oxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, quinolyl group, [1,5]naphthyridinyl group, [1,6]naphthyridinyl group, oxopiperidinyl group, oxodihydropyridinyl group, [1,2,4]triazolo[1,5-a]pyrimidinyl group, benzimidazolyl group, imidazo[4,5-c]pyridinyl group, quinoxalinyl group, pyrido[2,3-b]pyrazinyl group, pyrido[3,4-b]pyrazinyl group, pteridinyl group, pyrazino[2,3-b]pyrazinyl group, imidazo[4,5-b]pyrazinyl group, 2,2-dioxo-1,2,3,4-tetrahydropyrazino[2,3-c][1,2,6]thiadiazinyl group, 2-oxo-1,4-dihydropyrazino[2,3-d][1,3]oxazinyl group, 2-oxo-2,3-dihydroimidazo[4,5-b]pyrazinyl group, [1,2,5]thiadiazolo[3,4-b]pyrazinyl group, benzothiazolyl group, 4,5,6,7-tetrahydrobenzothiazolyl group, thiazolo[5,4-b]pyridinyl group, thiazolo[5,4-c]pyridinyl group, thiazolo[4,5-d]pyrimidinyl group, thiazolo[5,4-d]pyrimidinyl group, thiazolo[4,5-d]pyridazinyl group, thiazolo[4,5-b]pyrazinyl group, thiazolo[4,5-d][1,2,3]triazinyl group, 5-oxo-4,5-dihydrothiazolo[5,4-b]pyridinyl group, pyrazolo[3,4-d]thiazolyl group, 4,6-dioxo-5,6-dihydropyrrolo[3,4-d]thiazolyl group, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl group, 4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl group, 4-oxo-4,5-dihydrothiazolo[5,4-c]pyridinyl group, 7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidinyl group, 4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazinyl group, 7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazinyl group, 4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazinyl group, 4-oxo-3,4-dihydrothiazolo[4,5-d][1,2,3]triazinyl group, 5-oxo-[1,3,4]thiadiazolo[3,2-a]pyrimidinyl group, 7-oxo-[1,3,4]thiadiazolo[3,2-a]pyrimidinyl group, 4-oxo-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazinyl group, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazolyl group, and indenothiazolyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 26. The compound of claim 25, wherein the ring C2 is a thiazol-2-yl group optionally substituted by 1 to 5 substituents selected from group A′, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 27. The compound of claim 25, wherein the ring C2 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A′, and the heterocyclic group is selected from the group consisting of benzothiazol-2-yl group, 4,5,6,7-tetrahydrobenzothiazol-2-yl group, thiazolo[5,4-b]pyridin-2-yl group, thiazolo[5,4-c]pyridin-2-yl group, thiazolo[4,5-d]pyrimidin-2-yl group, thiazolo[5,4-d]pyrimidin-2-yl group, thiazolo[4,5-d]pyridazin-2-yl group, thiazolo[4,5-b]pyrazin-2-yl group, thiazolo[4,5-d][1,2,3]triazin-6-yl group, 5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl group, 1H-pyrazolo[3,4-d]thiazol-5-yl group, 4,6-dioxo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl group, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, 4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl group, 4-oxo-4,5-dihydrothiazolo[5,4-c]pyridin-2-yl group, 7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl group, 4-oxo-4,5-dihydrothiazolo[4,5-d]pyridazin-2-yl group, 7-oxo-6,7-dihydrothiazolo[4,5-d]pyridazin-2-yl group, 4,7-dioxo-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazin-2-yl group, 4-oxo-3,4-dihydrothiazolo[4,5-d][1,2,3]triazin-6-yl group, 5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, 7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl group, 4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl group, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl group, and indenothiazolyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 28. The compound of claim 25, wherein the ring C2 is a pyrazin-2-yl group optionally substituted by 1 to 5 substituents selected from group A′, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 29. The compound of claim 25, wherein the ring C2 is a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A′, and the heterocyclic group is selected from the group consisting of quinoxalin-2-yl group, pyrido[2,3-b]pyrazin-2-yl group, pyrido[2,3-b]pyrazin-3-yl group, pyrido[3,4-b]pyrazin-2-yl group, pteridin-6-yl group, pteridin-7-yl group, pyrazino[2,3-b]pyrazin-2-yl group, 1H-imidazo[4,5-b]pyrazin-5-yl group, 2,2-dioxo-1,2,3,4-tetrahydropyrazino[2,3-c][1,2,6]thiadiazin-7-yl group, 2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl group, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl group, and [1,2,5]thiadiazolo[3,4-b]pyrazinyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 30. The compound of claim 16, which is selected from the group consisting of (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide, (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-pyridin-3-ylamide, (R)-4-(4-propyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide, (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-pyrimidin-4-ylamide, 4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic acid tert-butyl ester, 4-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic acid hydrochloride, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide, (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-[1,3,4]thiadiazol-2-ylamide, 5-{[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester, (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-pyridin-4-ylamide, (R)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-isopropyl-benzylamide) 1-[1,3,4]oxadiazol-2-ylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-propyl-benzylamide) 1-pyridin-4-ylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-(4-propyl-benzylamide) 1-[1,3,4]thiadiazol-2-ylamide, (2-{[(R)-3-(4-propyl-benzyl carbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-{[4-(2-morpholin-4-yl-2-oxo-ethyl)-thiazol-2-yl]-amide} 3-(4-propyl-benzylamide), (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-{[4-(2-hydroxy-ethyl)-thiazol-2-yl]-amide} 3-(4-propyl-benzylamide), 5-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(5-hydroxymethyl-[1,3,4]thiadiazol-2-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-[(5-acetyl-[1,3,4]thiadiazol-2-yl)-amide] 3-[4-(1,1-difluoro-propyl)-benzylamide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-{[5-(1-hydroxy-1-methyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide}, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(5-methyl-[1,3,4]thiadiazol-2-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(2-methoxy-pyridin-4-yl)-amide], 4-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic acid tert-butyl ester, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-{[5-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-{[5-(4-hydroxy-piperidine-1-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-{[5-(morpholine-4-carbonyl)-[1,3,4]thiadiazol-2-yl]-amide}, 4-{[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carbonyl]-amino}-pyridine-2-carboxylic acid, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-[(2-carbamoyl-pyridin-4-yl)-amide] 3-[4-(1,1-difluoro-propyl)-benzylamide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(2-dimethylcarbamoyl-pyridin-4-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(2-hydroxymethyl-pyridin-4-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-[(2-cyclopropylcarbamoyl-pyridin-4-yl)-amide] 3-[4-(1,1-difluoro-propyl)-benzylamide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-{[2-(morpholine-4-carbonyl)-pyridin-4-yl]-amide}, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-{[2-(pyrrolidine-1-carbonyl)-pyridin-4-yl]-amide}, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-[(2-chloro-pyridin-4-yl)-amide] 3-[4-(1,1-difluoro-propyl)-benzylamide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-4-ylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(5-methyl-isoxazol-3-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(3-methyl-[1,2,4]thiadiazol-5-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(3-methyl-isoxazol-5-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[1,2,4]triazol-4-ylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-[(5-methyl-[1,3,4]thiadiazol-2-yl)-amide] 3-(4-pentafluoroethyl-benzylamide), (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(3-methyl-isothiazol-5-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-2-ylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(2-trifluoromethyl-pyridin-4-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(1H-[1,2,4]triazol-3-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(2H-tetrazol-5-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(2-methyl-thiazol-4-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-[(1-methyl-1H-pyrazol-3-yl)-amide], (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-thiazol-5-ylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-[4-(1,1-difluoro-propyl)-benzylamide] 1-{[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-amide}, and (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-[(5-bromo-[1,3,4]thiadiazol-2-yl)-amide] 3-(4-trifluoromethoxy-benzylamide), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 31. The compound of claim 17, which is selected from the group consisting of (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, 1-(4-iodo-benzenesulfonyl)-4-(2-piperidin-1-yl-acetyl)-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, 1-(4-iodo-benzenesulfonyl)-4-(2-morpholin-4-yl-acetyl)-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, 1-(4-iodo-benzenesulfonyl)-4-(2-pyridin-2-yl-acetyl)-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, 1-(4-iodo-benzenesulfonyl)-4-(2-pyridin-3-yl-acetyl)-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, (R)-1-(4-iodo-benzenesulfonyl)-4-(2-piperidin-1-yl-acetyl)-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, (R)-1-(4-iodo-benzenesulfonyl)-4-(2-pyrrolidin-1-yl-acetyl)-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, (R)-1-(4-iodo-benzenesulfonyl)-4-(2-morpholin-4-yl-acetyl)-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, (R)-4-(2-pyridin-3-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-morpholin-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-1H-imidazol-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-imidazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-[1,2,3]triazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-pyrazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-[1,2,4]triazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-[1,2,4]triazol-4-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-[1,2,3]triazol-2-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-1H-tetrazol-5-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2-tetrazol-2-yl-acetyl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (2-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic acid ethyl ester, (2-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic acid, (1-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-tetrazol-5-yl)-acetic acid ethyl ester, (1-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-tetrazol-5-yl)-acetic acid, 1-(4-iodo-benzenesulfonyl)-4-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-dimethylamino-benzylamide, (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-cyclopropyl-benzylamide, (2-{2-oxo-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-2H-tetrazol-5-yl)-acetic acid ethyl ester, (R)-4-[2-(5-methyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(2-tetrazol-2-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(2-imidazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(2-tetrazol-1-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (2-{2-oxo-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-2H-tetrazol-5-yl)-acetic acid, (2-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-tetrazol-5-yl)-acetic acid ethyl ester, (R)-4-[2-(5-methyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(5-phenyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(3-methyl-isoxazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(2-pyridin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(2-methyl-2H-tetrazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(1-methyl-1H-tetrazol-5-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (5-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-tetrazol-2-yl)-acetic acid ethyl ester, (5-{2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-2-oxo-ethyl}-tetrazol-1-yl)-acetic acid ethyl ester, (R)-4-[2-(5-isopropyl-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(5-isopropyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-{2-[5-(2-morpholin-4-yl-2-oxo-ethyl)-tetrazol-2-yl]-acetyl}-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(5-methyl-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-pentafluoroethyl-benzylamide, (R)-4-(2-pyrimidin-4-yl-acetyl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[2-(5-amino-tetrazol-2-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, and (R)-4-[2-(5-amino-tetrazol-1-yl)-acetyl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 32. The compound of claim 18, which is selected from the group consisting of 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid tert-butyl ester, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-4-(5-carbamoyl)-4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester, (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 2-[(R)-3-[(6-isopropyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(2-fluoro-4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 4-(4,5-dihydro-1H-imidazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, 4-(4,5-dihydro-thiazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, 1-(4-isopropyl-benzenesulfonyl)-4-(4-methyl-thiazol-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, 4-(4,5-dihydro-oxazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, 4-benzothiazol-2-yl-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, 1-(4-isopropyl-benzenesulfonyl)-4-(4-phenyl-thiazol-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, (R)-4-(2,5-dioxo-pyrrolidin-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, 4-(8H-indeno[1,2-d]thiazol-2-yl)-1-(4-isopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, 1-(4-isopropyl-benzenesulfonyl)-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, 2-[4-(4-isopropyl-benzenesulfonyl)-3-(4-trifluoromethyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-4-carboxylic acid ethyl ester, 2-[4-(4-isopropyl-benzenesulfonyl)-3-(4-trifluoromethyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-4-carboxylic acid, (R)-4-(4,5-dihydro-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-benzothiazol-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid methyl ester, {2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-acetic acid methyl ester, {2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-acetic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic acid ethyl ester, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid methyl ester, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid methyl ester, 6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic acid methyl ester, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid tert-butyl ester, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-tri-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid tert-butyl ester, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 4-hydroxy-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic acid ethyl ester, 6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic acid tert-butyl ester, 6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-nicotinic acid trifluoroacetate, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid tert-butyl ester, 2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-propyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, 2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic acid benzyl ester, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic acid methyl ester, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-pyrimidine-5-carboxylic acid, 4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, 4-methyl-2-[(R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic acid, 2-[(R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 2-[(R)-4-(4-isopropyl-benzenesulfonyl)-3-(4-isopropyl-benzyl carbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-4-(2-oxo-pyrrolidin-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-isonicotinic acid trifluoroacetate, (R)-4-(1-methyl-1H-imidazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(1H-imidazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(4-methyl-5-methylcarbamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(5-dimethylcarbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, 2-[(R)-3-(4-cyclopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 4-hydroxy-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrimidine-5-carboxylic acid, ({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-acetic acid tert-butyl ester, 3-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid tert-butyl ester, ({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-acetic acid, 3-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid, (R)-4-(5-nitro-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, 4-ethyl-2-[(R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-(4-isopropyl-2-methyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 4-methyl-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-(4-ethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-4-(5-amino-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-2-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid, (S)-2-({2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-4-methyl-oxazole-5-carboxylic acid trifluoroacetate, (R)-4-(5-bromo-2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(2H-[1,2,4]triazol-3-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 6-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic acid, (R)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic acid 5′-amide 3-(4-isopropyl-benzylamide), 4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid hydrochloride, 3-{2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-4-yl}-propionic acid, 2-[(R)-3-(4-cyclopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-carboxylic acid, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 2-[(R)-3-[(6-dimethylamino-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 4-methyl-2-[(R)-3-[(6-propyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-[(6-azetidin-1-yl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 4-methyl-2-[(R)-3-[(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-4-methoxymethyl-thiazole-5-carboxylic acid, 2-[(R)-3-(4-azetidin-1-yl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-3-(4-dimethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 2-[(R)-3-benzylcarbamoyl-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-4-(5-carbamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-3-[(6-dimethylamino-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-3-[(6-isopropyl-pyridin-3-ylmethyl)-carbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 4-methyl-2-[(R)-3-(4-pyrrolidin-1-yl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic acid, 4-methyl-2-[(R)-3-phenethylcarbamoyl-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, (R)-6′-amino-3′-chloro-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester, (R)-6′-bromo-3′-chloro-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester, (R)-3-(4-isopropyl-benzylcarbamoyl)-3′,6′-dimethyl-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-6′-amino-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester, 2-[(R)-3-[4-(ethyl-methyl-amino)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 2-[(R)-3-(4-diethylamino-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, 5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2H-pyrazole-3-carboxylic acid, 4-chloro-5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2H-pyrazole-3-carboxylic acid, (R)-3-(4-isopropyl-benzylcarbamoyl)-3′-methyl-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester, (R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-5-methyl-thiazole-4-carboxylic acid, 5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-1-methyl-1H-pyrazole-3-carboxylic acid, (R)-4-(4-propyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-3-(2-methyl-4-propyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 2-[(R)-3-(4-ethoxy-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-6′-amino-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester, 5-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-2-methyl-2H-pyrazole-3-carboxylic acid, (R)-4-(5-methanesulfonylaminocarbonyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(5-methanesulfonylaminocarbonyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, 2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-6′-methyl-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 2-[(R)-3-(4-methoxymethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-4-(5-hydroxymethyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-trifluoromethyl-thiazole-5-carboxylic acid, (R)-4-(6-hydroxy-5-methyl-pyridazin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(5-amino-pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-5′-amino-4-(4-trifluoromethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-isopropyl-benzylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-propyl-benzylamide, (R)-3-(4-methoxymethyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-carboxylic acid, (R)-3-(2-chloro-4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-4-(4-ethyl-benzenesulfonyl)-5′-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-propyl-benzylamide, (R)-3-(2-chloro-4-propyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic acid methyl ester, 4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic acid, {4-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl}-pyrazol-1-yl]-acetic acid, 4-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic acid amide 4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(3-propyl-4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, (R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-4-(5-dimethylaminomethyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(4-methyl-5-methylaminomethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-6′-amino-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester, 2-[(R)-4-(3-fluoro-4-trifluoromethoxy-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-4-methyl-thiazole-5-carboxylic acid, (R)-4-(4-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-6′-acetylamino-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester, (R)-4-(5-oxo-4,5-dihydro-[1,3,4]thiadiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(5-methyl-1H-pyrazol-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-isopropyl-benzylamide, (R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-5′-amino-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-propyl-benzylamide, (R)-4-(4-methyl-5-pyrrolidin-1-ylmethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester, 5-hydroxymethyl-2-[(R)-3-(4-isopropyl-benzylcarbamoyl)-4-(4-propyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic acid, 5-methoxymethyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic acid, 5-hydroxymethyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-4-carboxylic acid, (R)-5′-dimethylaminomethyl-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-3-carboxylic acid 4-propyl-benzylamide, (R)-5′-methanesulfonylamino-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-propyl-benzylamide, (R)-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(6-hydroxy-pyridazin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, 6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridazine-3-carboxylic acid amide, (R)-4-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-propyl-benzylamide, (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-5′-pyrrolidin-1-ylmethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-3-carboxylic acid 4-tert-butyl-benzylamide, (R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(5-benzyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(4,5-bis-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(3-methyl-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-ethyl-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-4-(5-hydroxymethyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(6-chloro-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-pyrimidin-4-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(4,6-dioxo-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(3-methyl-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(5-cyano-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(4-oxo-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-pyrimidin-4-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(2-hydroxy-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, 4-amino-2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid ethyl ester, (R)-4-(2-amino-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(4-amino-pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic acid 5′-amide 3-[4-(1,1-difluoro-propyl)-benzylamide], 2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester, (R)-4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-5′-cyano-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-3-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-5′-morpholin-4-ylmethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-tert-butyl-benzylamide, (R)-5′-(4-methyl-piperazin-1-ylmethyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-tert-butyl-benzylamide, (R)-5′-dimethylaminomethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(3-acetylamino-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(4-oxo-4,5-dihydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(5-methanesulfonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, 2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid ethylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, 2-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-4-hydroxymethyl-thiazole-5-carboxylic acid, (R)-6′-amino-5′-hydroxymethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(6-amino-pyrimidin-4-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(3-methoxy-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(2-oxo-1,4-dihydro-2H-pyrazino[2,3-d][1,3]oxazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(ethyl-methyl-amino)-benzylamide, 5-[(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridine-2-carboxylic acid, (R)-4-(3-methoxy-[1,2,4]thiadiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-chloro-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (6-dimethylamino-pyridin-3-ylmethyl)-amide, 5-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyridine-2-carboxylic acid, (R)-4-quinoxalin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-6′-amino-5′-aminomethyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (benzoxazol-2-ylmethyl)-amide, (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(6-hydroxy-[1,2,5]thiadiazolo[3,4-b]pyrazin-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(2,2-dioxo-1,2,3,4-tetrahydro-2λ⁶-pyrazino[2,3-c][1,2,6] thiadiazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-ethoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-thiophen-2-yl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-bromo-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-cyclopropyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-methoxymethyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-methoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid ([2,2′]bithiophenyl-5-ylmethyl)-amide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-methylsulfanyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (1-propyl-1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (biphenyl-4-ylmethyl)-amide, (R)-4-(4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(1H-imidazo[4,5-b]pyrazin-5-yl)-1-(4-tri fluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (2-oxo-1-propyl-1,2-dihydro-pyridin-4-ylmethyl)-amide, (R)-1-(4-bromo-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(6-bromo-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(7-bromo-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(4-bromo-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-carboxylic acid, (R)-4-(6-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-tert-butyl-benzylamide, (R)-4-pyrazino[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[1,2,5]thiadiazolo[3,4-b]pyrazin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(2-methyl-pteridin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, 2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic acid ethyl ester, (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-tert-butyl-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-chloro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-nitro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(4-tert-butyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-carboxylic acid, (R)-4-(biphenyl-4-sulfonyl)-3-(4-propyl-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-carboxylic acid, (R)-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-iodo-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-7-yl-1-(4-thiophen-2-yl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, 3-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic acid ethyl ester, 3-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic acid, 2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-6-carboxylic acid, (R)-1-(4-chloro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-tert-butyl-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-thiazolo[5,4-c]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (6-propyl-pyridin-3-ylmethyl)-amide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 3-amino-4-propyl-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 3-hydroxy-4-propyl-benzylamide, (R)-1-(2′-hydroxy-biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(3′-hydroxy-biphenyl-4-sulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-nitro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(biphenyl-4-sulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, 5-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiophene-2-carboxylic acid tert-butyl ester, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide, (4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-2-yloxy)-acetic acid, (4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-3-yloxy)-acetic acid, (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-dimethylamino-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-thiazolo[5,4-b]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-[1,6]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(5-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(8-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-pyrolidin-1-yl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, trans-[4-(4-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-phenyl)-cyclohexyl]-acetic acid, (R)-4-pyrido[3,4-b]pyrazin-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-morpholin-4-yl-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-methoxy-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrido[2,3-b]pyrazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrazino[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-[4-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-(4-chloro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 4′-{(R)-2-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-pteridin-7-yl-piperazine-1-sulfonyl}-biphenyl-3-carboxylic acid, (R)-1-(4-nitro-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-pyrrolidin-1-yl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(3H-imidazo[4,5-c]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrido[3,4-b]pyrazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(1H-benzimidazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-1-[4-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzenesulfonyl]-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrido[2,3-b]pyrazin-3-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrido[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-pyrido[2,3-b]pyrazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(2,2,2-trifluoro-ethoxy)-benzylamide, (methyl-{4-[(R)-4-pyrido[3,4-b]pyrazin-2-yl-2-(4-trifluoromethoxy-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenyl}-amino)-acetic acid ethyl ester, (methyl-[4-[(R)-4-pyrido[3,4-b]pyrazin-2-yl-2-(4-trifluoromethoxy-benzylcarbamoyl)-piperazine-1-sulfonyl]-phenyl]-amino)-acetic acid, (R)-4-(5-chloro-quinoxalin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(2-methyl-pteridin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[5,4-c]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pyrido[2,3-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pyrido[2,3-b]pyrazin-3-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[1,6]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethylsulfanyl-benzylamide, 4-{5-[(R)-2-(4-propyl-benzylcarbamoyl)-4-pteridin-7-yl-piperazine-1-sulfonyl]-2-trifluoromethoxy-phenyl}-butyric acid, 6-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-nicotinic acid, (R)-4-thiazolo[5,4-b]pyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-iodo-benzenesulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-1-(3′-hydroxy-biphenyl-4-sulfonyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-2-carboxylic acid 4-propyl-benzylamide, {4′-[(R)-2-(4-propyl-benzylcarbamoyl)-4-pyrido[3,4-b]pyrazin-2-yl-piperazine-1-sulfonyl]-biphenyl-3-yloxy}-acetic acid, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic acid, 3-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic acid, (R)-4-quinoxalin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(4-oxo-3,4-dihydro-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(4-ethyl-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-4-(4-pyrrolidin-1-yl-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-1-(4-nitro-benzenesulfonyl)-4-pteridin-7-yl-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[1,5]naphthyridin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-b]pyrazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamide, (R)-4-(4-ethyl-benzenesulfonyl)-5′-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 2,4,6-trichloro-benzylamide, (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(2-trifluoromethyl-pteridin-7-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(8-bromo-pyrido[3,4-b]pyrazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5,7-dichloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(4,7-dioxo-4,5,6,7-tetrahydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (adamantan-1-ylmethyl)-amide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid amide, 3-{2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazin-8-yl}-propionic acid, (R)-6′-methyl-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, (R)-4-[8-(2-carbamoyl-ethyl)-pyrido[3,4-b]pyrazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (3-phenyl-propyl)-amide, (R)-1-(4-ethyl-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(8-bromo-pyrido[3,4-b]pyrazin-2-yl)-1-(4-ethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic acid, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, 3-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-quinoxaline-5-carboxylic acid, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-quinoxaline-5-carboxylic acid, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-benzothiazole-4-carboxylic acid, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, 2-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-nicotinic acid, 5-fluoro-2-methyl-6-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-nicotinic acid, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, (R)-1-(4-nitro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, 3-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-propionic acid, (R)-4-(4-methyl-5-sulfamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(4-methyl-5-methylsulfamoyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(5-dimethylsulfamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-(5-acetylsulfamoyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-1-(4-nitro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-3-[4-(1,1-difluoro-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, (R)-4-(4-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-dimethyl-propyl)-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-butyl-benzylamide, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, 2-[(R)-4-(4-nitro-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, 2-[(R)-4-(4-tert-butyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, 2-[(R)-4-(4-chloro-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, {4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-oxo-acetic acid ethyl ester, 4-chloro-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, {4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-oxo-acetic acid, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (2-phenyl-cyclopropylmethyl)-amide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(2-methoxy-1,1-dimethyl-ethyl)-benzylamide, (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic acid 5′-ethylamide 3-(4-trifluoromethoxy-benzylamide), (R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3,5′-dicarboxylic acid 5′-tert-butylamide 3-(4-trifluoromethoxy-benzylamide), 2-[(R)-3-[4-(1,1-dimethyl-propyl)-benzylcarbamoyl]-4-(4-ethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, 2-[(R)-3-(4-butyl-benzylcarbamoyl)-4-(4-ethyl-benzenesulfonyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid, hydroxy-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-acetic acid ethyl ester, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (5-propyl-thiophen-2-ylmethyl)-amide, (R)-4-(4-methyl-5-methylaminooxalyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic acid ethyl ester, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic acid, (R)-1-(4-fluoro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid methylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid dimethylamide, (R)-4-pteridin-7-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (1-phenyl-azetidin-3-ylmethyl)-amide, 4-chloro-2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, (R)-4-(7-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(4-hydroxymethyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-pyrido[3,4-b]pyrazine-8-carboxylic acid isopropylamide, (R)-4-(8-cyano-pyrido[3,4-b]pyrazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-chloro-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic acid, 7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic acid methylamide, 7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-6,7-dihydro-thiazolo[4,5-d]pyridazine-4-carboxylic acid amide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-hydroxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 7-chloro-2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic acid ethyl ester, (R)-1-(4-bromo-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1-methoxymethyl-cyclopropyl)-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(ethyl-methyl-amino)-benzylamide, (R)-1-(4-methoxy-benzenesulfonyl)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[5,4-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5,7-dihydroxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 4-chloro-2-[(R)-3-[4-(1,1-dimethyl-propyl)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic acid ethyl ester, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic acid, (R)-4-(4-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(7-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyridazin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1,2,2-tetrafluoro-ethoxy)-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (3-phenyl-cyclobutylmethyl)-amide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (naphthalen-2-ylmethyl)-amide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(6-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-chloro-4-methyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (4-methyl-2-propyl-thiazol-5-ylmethyl)-amide, (R)-4-(5-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(5-bromo-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic acid amide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic acid methylamide, (R)-4-(4-methyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-methyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methyl-thiazolo[5,4-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(6-oxo-piperidin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide hydrochloride, (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(5-methoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyridazine-4-carboxylic acid dimethylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(1,1-difluoro-propyl)-benzylamide, (R)-4-(4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(difluoro-methoxy-methyl)-benzylamide, (R)-4-(7-oxo-6,7-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-methoxymethyl-benzylamide, (R)-4-(4-hydroxymethyl-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-chloro-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-amino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-methoxy-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-dimethylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(2-hydroxy-ethylamino)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylic acid methyl ester, (R)-4-(5-ethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-ethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(3-trifluoromethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-methyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-(ethyl-methyl-amino)-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-thiazolo[4,5-d]pyrimidin-2-yl-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-amino-5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-chloro-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-methoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-fluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-fluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-cyclopropyl-benzylamide, (R)-4-(5-fluoro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benz enesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-isopropylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-bromo-7-diethylamino-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-cyclopropyl-benzylamide, (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-acetyl-4-methyl-thiazol-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic acid amide, (R)-4-(1,3-dimethyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-amino-5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-isopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(4-chloro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d][1,2,3]triazin-6-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid (indolizin-2-ylmethyl)-amide, 7-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylic acid methylamide, (R)-4-(5-isopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-chloro-2-diethylamino-thiazolo[4,5-d]pyrimidin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(3-hydroxy-3-methyl-but-1-ynyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-ethynyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-pentafluorosulfanyl-benzylamide, (R)-4-(5-chloro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-2-fluoro-benzylamide, (R)-4-thiazolo[4,5-d]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-2-fluoro-benzylamide, (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-[4-(2-hydroxy-ethylamino)-thiazolo[4,5-d][1,2,3]triazin-6-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-5-trifluoromethyl-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-thiazolo[4,5-d][1,2,3]triazin-6-yl-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic acid ethyl ester, (R)-4-(5-hydroxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(4-methoxy-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-cyclopropylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-3-(4-trifluoromethoxy-benzylcarbamoyl)-4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic acid amide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-difluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-amino-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-methoxy-5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-tert-butyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-tert-butyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxyli c acid 4-trifluoromethoxy-benzylamide, (R)-4-(6-chloro-5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 5-methyl-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-7-carboxylic acid amide, (R)-4-(5-methyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(4-oxo-3-trifluoromethyl-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic acid, (R)-4-(4-amino-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(4-methoxy-thiazolo[4,5-d][1,2,3]triazin-6-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyano-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-ethyl-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-oxo-7-trifluoromethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-2-fluoro-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic acid dimethylamide, (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-2-fluoro-benzylamide, (R)-4-(5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-2-fluoro-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-2-fluoro-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic acid methylamide, (R)-4-[5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-acetyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-methyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzenesulfonyl]-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-hydroxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[4,5-d]pyrimidine-5-carboxylic acid methoxy-methyl-amide, (R)-4-(7-amino-5-methoxymethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-pyrrolidin-1-ylmethyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(1-hydroxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide, (R)-4-(5-oxo-4,5-dihydro-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-difluoromethoxy-benzenesulfonyl)-4-(7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic acid ethyl ester, 2-[(R)-4-(4-ethyl-benzenesulfonyl)-3-(4-propyl-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic acid, (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(7-oxo-5-trifluoromethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(5-cyclobutyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(2-methoxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(2-methoxy-ethyl)-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclobutyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide, (R)-4-[5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(1-methoxymethyl-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(1-hydroxymethyl-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(2-hydroxy-ethyl)-4-oxo-4,5-dihydro-thiazolo[4,5-d]pyridazin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(1-methoxy-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[5-(1-hydroxy-cyclopropyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-6-carboxylic acid tert-butyl ester, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-6-carboxylic acid, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic acid ethyl ester, 2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic acid, (R)-1-(4-trifluoromethyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide, (R)-4-(5-oxo-4,5-dihydro-thiazolo[5,4-b]pyridin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-difluoromethoxy-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-isopropyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-isopropyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-benzylamide, (R)-4-(7-amino-5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-[7-amino-5-(1-hydroxy-1-methyl-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, hydroxy-{4-methyl-2-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazol-5-yl}-acetic acid, 4-chloro-2-[(R)-3-[4-(ethyl-methyl-amino)-benzylcarbamoyl]-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid, {5-methyl-3-[(R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-pyrazol-1-yl}-acetic acid, [(R)-3-(4-tert-butyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylmethyl]-triethyl-ammonium trifluoro-methanesulfonate, (R)-4-[5-(2-hydroxy-ethyl)-thiazolo[4,5-d]pyrimidin-2-yl]-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-cyclopropyl-benzenesulfonyl)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-1-(4-cyclopropyl-benzenesulfonyl)-4-(5-trifluoromethyl-thiazolo[4,5-d]pyrimidin-2-yl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzylamide, 2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic acid, (R)-4-(5-hydroxymethyl-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, {4-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-4H-thiazolo[4,5-d]pyridazin-5-yl}-acetic acid, (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, 2-[(R)-3-(4-difluoromethoxy-3-fluoro-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazolo[5,4-c]pyridine-7-carboxylic acid, (R)-4-(5-cyclopropyl-thiazolo[4,5-d]pyrimidin-2-yl)-1-(2-fluoro-4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide, (R)-3-(4-difluoromethoxy-3-fluoro-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid, 3-{4-oxo-2-[(R)-4-(4-trifluoromethoxy-benzenesulfonyl)-3-(4-trifluoromethoxy-benzylcarbamoyl)-piperazin-1-yl]-4H-thiazolo[4,5-d]pyridazin-5-yl}propionic acid, (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide, and (R)-4-(5-cyclopropyl-7-oxo-6,7-dihydro-thiazolo[4,5-d]pyrimidin-2-yl)-1-(4-trifluoromethyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzylamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
 33. A pharmaceutical composition comprising a compound of any one of claims 15 to 18 or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. 34.-43. (canceled)
 44. A method for treating hepatitis C in a mammal, which method comprises administering an effective amount of a compound represented by the formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal with hepatitis C, thereby treating hepatitis C in the mammal:

wherein ring A is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and R is a hydrogen atom, —COR¹, —COOR², —CONR³R⁴, —SO₂R⁵, —CO—COOR⁶, —CO—CH═CH—COOR¹¹, —CO—(CH₂)_(a)—NH—R⁷, —CO—(CH₂)_(b)—NHCOR⁸, —CO—(CH₂)_(c)—NHCOOR⁹ (wherein R¹ to R⁹ and R¹¹ are the same or different and each is a hydrogen atom or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, and a, b and c are the same or different and each is an integer of 1 to 4), —CO—CONH₂, —C(═NH)NH₂, —C(═S)NH₂, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, or

wherein X is a bond, C₁₋₄ alkylene, —CO—(CH₂)_(p)—, —CONR¹⁰—(CH₂)_(q)—, —CO—(CH₂)_(r)—O—(CH₂)_(s)—, —CO—(CH₂)_(t)—NH—(CH₂)_(u)—, —CO—(CH₂)_(v)—CONH—(CH₂)_(w)—, or —CO—NH—SO₂—, ring C is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), R¹⁰ is a hydrogen atom, or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, p, q, r, s, u, v and w are the same or different and each is 0 or an integer of 1 to 4, and t is an integer of 1 to 4, group A: halogen atom, nitro group, cyano group, OR^(a1) —SR^(a2), —NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅ (wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ Carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, group B: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkoxy group, amino group, C₁₋₄ alkylamino group, di(C₁₋₄ alkyl)amino group, carboxyl group, C₁₋₄ alkoxy-carbonyl group, carbamoyl group, C₁₋₄ alkylamino-carbonyl group, di(C₁₋₄ alkyl)amino-carbonyl group, heterocyclyl-carbonyl group, and tri(C₁₋₄ alkyl)ammoniumyl group (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group C: halogen atom, cyano group, hydroxyl group, carboxyl group, C₁₋₄ alkyl group, halogeno C₁₋₄ alkyl group, hydroxy C₁₋₄ alkyl group, carboxy C₁₋₄ alkyl group, C₁₋₄ alkoxy C₁₋₄ alkyl group, C₁₋₄ alkoxy group, and carboxy C₁₋₄ alkoxy group.
 45. The method of claim 44 further comprising administering an effective amount of at least one pharmaceutical agent selected from the group consisting of a different antiviral agent, an antiinflammatory agent and an immunostimulant to the mammal.
 46. The method of claim 44 further comprising administering an effective amount of interferon to the mammal.
 47. A method for inhibiting HCV polymerase in a mammal, which comprises administering an effective amount of a compound represented by the formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal, thereby inhibiting HCV polymerase in the mammal:

wherein ring A is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and R is a hydrogen atom, —COR¹, —COOR², —CONR³R⁴, —SO₂R⁵, —CO—COOR⁶, —CO—CH═CH—COOR¹¹, —CO—(CH₂)_(a)—NH—R⁷, —CO—(CH₂)_(b)—NHCOR⁸, —CO—(CH₂)_(c)—NHCOOR⁹ (wherein R¹ to R⁹ and R¹¹ are the same or different and each is a hydrogen atom or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, and a, b and c are the same or different and each is an integer of 1 to 4), —CO—CONH₂, —C(═NH)NH₂, —C(═S)NH₂, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, or

wherein X is a bond, C₁₋₄ alkylene, —CO—(CH₂)_(p)—, —CONR¹⁰—(CH₂)_(q)—, —CO—(CH₂)_(r)—O—(CH₂)_(s)—, —CO—(CH₂)_(t)—NH—(CH₂)_(u)—, —CO—(CH₂)_(v)—CONH—(CH₂)_(w)—, or —CO—NH—SO₂—, ring C is a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), R¹⁰ is a hydrogen atom, or a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, p, q, r, s, u, v and w are the same or different and each is 0 or an integer of 1 to 4, and t is an integer of 1 to 4, group A: halogen atom, nitro group, cyano group, —OR^(a1), —SR^(a2), NR^(a3)R^(a4), —NHCOR^(a5), —NHSO₂R^(a14), —COOR^(a6), —CONR^(a7)R^(a8), —SO₂NR^(a9)R^(a10), —SO₂NHCOR^(a15), —COR^(a11), —SO₂R^(a12), —CONHSO₂R^(a13), —COCOOR^(a16), —COCONR^(a17)R^(a18), —CONR^(a19)(OR^(a20)), —SF₅ (wherein R^(a1) to R^(a20) are the same or different and each is a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C), a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C₂₋₁₀ alkynyl group optionally substituted by 1 to 5 substituents selected from the following group B a C₃₋₁₂ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), a C₆₋₁₂ aryl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, group B: halogen atom, cyano group, hydroxyl group, C₁₋₄ alkoxy group, amino group, C₁₋₄ alkylamino group, di(C₁₋₄ alkyl)amino group, carboxyl group, C₁₋₄ alkoxy-carbonyl group, carbamoyl group, C₁₋₄ alkylamino-carbonyl group, di(C₁₋₄ alkyl)amino-carbonyl group, heterocyclyl-carbonyl group, and tri(C₁₋₄ alkyl)ammoniumyl group (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), group C: halogen atom, cyano group, hydroxyl group, carboxyl group, C₁₋₄ alkyl group, halogeno C₁₋₄ alkyl group, hydroxy C₁₋₄ alkyl group, carboxy C₁₋₄ alkyl group, C₁₋₄ alkoxy C₁₋₄ alkyl group, C₁₋₄ alkoxy group, and carboxy C₁₋₄ alkoxy group.
 48. The method of claim 47 further comprising administering an effective amount of at least one pharmaceutical agent selected from the group consisting of a different antiviral agent, an antiinflammatory agent and an immunostimulant to the mammal.
 49. The method of claim 47 further comprising administering an effective amount of interferon to the mammal.
 50. (canceled)
 51. (canceled) 